Category Archives: apoptosis induction

anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, apoptosis induction, Apoptotic, AR, BAX, Bcl-2, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, EJ, T24, 5637, G2/M, growth-inhibitory, HCT-116, L1210, MDA-MB-231, Melanoma, MT-4, Pro-apoptotic, pro-oxidative, Prostate cancer, Rectal cancer, ROS, S, XIAP

Sanguinarine (See also chelerythrine)

Cancer:
Prostate, bladder, breast, colon, melanoma, leukemia

Action: Pro-oxidative, anti-inflammatory, apoptosis induction

AR+/AR- Prostate Cancer

Sanguinarine, a benzophenanthridine alkaloid derived from the bloodroot plant Sanguinaria canadensis (L.), has been shown to possess anti-microbial, anti-inflammatory, anti-cancer and anti-oxidant properties. It has been shown that sanguinarine possesses strong anti-proliferative and pro-apoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, the anti-proliferative properties of sanguinarine against prostate cancer were also examined.

The mechanism of the anti-proliferative effects of sanguinarine against prostate cancer were examined by determining the effect of sanguinarine on critical molecular events known to regulate the cell-cycle and the apoptotic machinery.

A highlight of this study was the fact that sanguinarine induced growth-inhibitory and anti-proliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell-cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer (Adhami et al., 2004).

Breast Cancer

The effects of this compound were examined on reactive oxygen species (ROS) production and its association with apoptotic tumor cell death using a human breast carcinoma MDA-MB-231 cell line. Cytotoxicity was evaluated by trypan blue exclusion methods. Apoptosis was detected using DAPI staining, agarose gel electrophoresis and flow cytometer. The expression levels of proteins were determined by Western blot analyzes and caspase activities were measured using colorimetric assays.

These observations clearly indicate that ROS is involved in the early molecular events in the sanguinarine-induced apoptotic pathway. Data suggests that sanguinarine-induced ROS are key mediators of MMP collapse, which leads to the release of cytochrome c followed by caspase activation, culminating in apoptosis (Choi, Kim, Lee & Choi, 2008).

Leukemia

Sanguinarine, chelerythrine and chelidonine are isoquinoline alkaloids derived from the greater celandine. They possess a broad spectrum of pharmacological activities. It has been shown that their anti-tumor activity is mediated via different mechanisms, which can be promising targets for anti-cancer therapy.

This study focuses on the differential effects of these alkaloids upon cell viability, DNA damage, and nucleus integrity in mouse primary spleen and lymphocytic leukemic cells, L1210. Sanguinarine and chelerythrine produced a dose-dependent increase in DNA damage and cytotoxicity in both primary mouse spleen cells and L1210 cells. Chelidonine did not show a significant cytotoxicity or damage DNA in both cell types, but completely arrested growth of L1210 cells.

Data suggests that cytotoxic and DNA-damaging effects of chelerythrine and sanguinarine are more selective against mouse leukemic cells and primary mouse spleen cells, whereas chelidonine blocks proliferation of L1210 cells. The action of chelidonine on normal and tumor cells requires further investigation (Kaminsky, Lin, Filyak, & Stoika, 2008).

T-lymphoblastic Leukemia

Apoptogenic and DNA-damaging effects of chelidonine (CHE) and sanguinarine (SAN), two structurally related benzophenanthridine alkaloids isolated from Chelidonium majus, were compared. Both alkaloids induced apoptosis in human acute T-lymphoblastic leukemia MT-4 cells. Apoptosis induction by CHE and SAN in these cells were accompanied by caspase-9 and -3 activation and an increase in the pro-apoptotic Bax protein. An elevation in the percentage of MT-4 cells possessing caspase-3 in active form after their treatment with CHE or SAN was in parallel to a corresponding increase in the fraction of apoptotic cells.

The involvement of the mitochondria in apoptosis induction by both alkaloids was supported by cytochrome C elevation in cytosol, with an accompanying decrease in cytochrome C content in the mitochondrial fraction. At the same time, two alkaloids under study differed drastically in their cell-cycle phase-specific effects, since only CHE arrested MT-4 cells at the G2/M phase. It was previously demonstrated, that CHE, in contrast to SAN, does not interact directly with DNA. (Philchenkov, Kaminskyy, Zavelevich, & Stoika, 2008).

Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. This study found that sanguinarine and chelerythrine induced apoptosis in human CEM T-leukemia cells, accompanied by an early increase in cytosolic cytochrome C that precedes caspases-8, -9 and -3 processing. Effects of sanguinarine and chelerythrine on mitochondria were confirmed by clear changes in morphology (3h), however chelidonine did not affect mitochondrial integrity.

Sanguinarine and chelerythrine also caused marked DNA damage in cells after 1h, but a more significant increase in impaired cells occurred after 6h. Chelidonine induced intensive DNA damage in 15–20% cells after 24h. Results demonstrated that rapid cytochrome C release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8 (Kaminskyy, Kulachkovskyy & Stoika, 2008).

Colorectal Cancer

The effects of sanguinarine, a benzophenanthridine alkaloid, was examined on reactive oxygen species (ROS) production, and the association of these effects with apoptotic cell death, in a human colorectal cancer HCT-116 cell line. Sanguinarine generated ROS, followed by a decrease in mitochondrial membrane potential (MMP), activation of caspase-9 and -3, and down-regulation of anti-apoptotic proteins, such as Bcl2, XIAP and cIAP-1. Sanguinarine also promoted the activation of caspase-8 and truncation of Bid (tBid).

Observations clearly indicate that ROS, which are key mediators of Egr-1 activation and MMP collapse, are involved in the early molecular events in the sanguinarine-induced apoptotic pathway acting in HCT-116 cells (Han, Kim, Yoo, & Choi, 2013).

Bladder Cancer

Although the effects of sanguinarine, a benzophenanthridine alkaloid, on the inhibition of some kinds of cancer cell growth have been established, the underlying mechanisms are not completely understood. This study investigated possible mechanisms by which sanguinarine exerts its anti-cancer action in cultured human bladder cancer cell lines (T24, EJ, and 5637). Sanguinarine treatment resulted in concentration-response growth inhibition of the bladder cancer cells by inducing apoptosis.

Taken together, the data provide evidence that sanguinarine is a potent anti-cancer agent, which inhibits the growth of bladder cancer cells and induces their apoptosis through the generation of free radicals (Han et al., 2013).

Melanoma

Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Current study has found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨ m), released cytochrome C and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Thus, pre-treatment with the thiol anti-oxidants NAC and GSH abrogated the killing activity of sanguinarine. Collectively, data suggests that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress (Burgeiro, Bento, Gajate, Oliveira, & Mollinedo, 2013).

References

Adhami YM, Aziz MH, Reagan-Shaw SR, et al. (2004). Sanguinarine causes cell-cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. Mol Cancer Ther, 3:933


Burgeiro A, Bento AC, Gajate C, Oliveira PJ, Mollinedo F. (2013). Rapid human melanoma cell death induced by sanguinarine through oxidative stress. European Journal of Pharmacology, 705(1-3), 109-18. doi: 10.1016/j.ejphar.2013.02.035.


Choi WY, Kim GY, Lee WH, Choi YH. (2008). Sanguinarine, a benzophenanthridine alkaloid, induces apoptosis in MDA-MB-231 human breast carcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. Chemotherapy, 54(4), 279-87. doi: 10.1159/000149719.


Han MH, Kim GY, Yoo YH, Choi YH. (2013). Sanguinarine induces apoptosis in human colorectal cancer HCT-116 cells through ROS-mediated Egr-1 activation and mitochondrial dysfunction. Toxicology Letters, 220(2), 157-66. doi: 10.1016/j.toxlet.2013.04.020.


Han MH, Park C, Jin CY, et al. (2013). Apoptosis induction of human bladder cancer cells by sanguinarine through reactive oxygen species-mediated up-regulation of early growth response gene-1. PLoS One, 8(5), e63425. doi: 10.1371/journal.pone.0063425.


Kaminskyy V, Lin KW, Filyak Y, Stoika R. (2008). Differential effect of sanguinarine, chelerythrine and chelidonine on DNA damage and cell viability in primary mouse spleen cells and mouse leukemic cells. Cell Biology International, 32(2), 271-277.


Kaminskyy V, Kulachkovskyy O, Stoika R. (2008) A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicology Letters, 177(3), 168-81. doi: 10.1016/j.toxlet.2008.01.009.


Philchenkov A, Kaminskyy V, Zavelevich M, Stoika R. (2008). Apoptogenic activity of two benzophenanthridine alkaloids from Chelidonium majus L. does not correlate with their DNA-damaging effects. Toxicology In Vitro, 22(2), 287-95.

Anti-hemolytic, anti-oxidant, anti-proliferative, apoptosis, apoptosis induction, apoptosis-inducing, Chapter 7 Isolates and Cancer Research, Gastric cancer or Stomach cancer

Ferula Gummosa Boiss Extract

Cancer: Gastric

Action: Anti-oxidant, Anti-hemolytic

Ferula gummosa Boiss. (Barije) is an Iranian endemic plant growing in the northern mountainous regions. The gum extracted from the aerial parts of the plant has been traditionally used in the treatment of wounds, stomach pain and chorea. For the first time, anti-proliferative activity and apoptosis-inducing effects of ethanol extracts of the F. gummosa Boiss. leaf and flower were examined.

Gastric Cancer

The ethanol extracts were examined for their anti-proliferative and apoptosis inducing activity in human gastric cancer cell line, AGS, using concentrations from 10–70µg/mL.   F. gummosa Boiss. extracts inhibited the cell proliferation of AGS cell line in a dose-dependent manner with an IC50 of 37.47µg/mL for flower and 32.99µg/mL for leaf extracts. F. gummosa Boiss. extracts also induced apoptosis as shown by analysis of DNA fragmentation and plasma membrane translocation of phosphatidyl serine. F. gummosa Boiss. extracts exerted anti-proliferative as well as apoptosis induction effect in gastric cancer cell line. Further studies are needed for elucidation of the biochemical performance details and biological activity of the oleo gum-resin from Ferula gummosa Boiss which has shown acetylcholinesterase (AChE) inhibitory activity (Adhami et al., 2013).

Anti-oxidant, Anti-hemolytic activities

F. gummosa Boiss root showed different level anti-oxidant and anti-hemolytic activities. Biological effects may be attributed, at least in part, to the presence of phenols and flavonoids in the extract (Ebrahimzadeh et al., 2011).

References

Adhami HR, Scherer U, Kaehlig H, et al. (2013). Combination of bioautography with HPTLC-MS/NMR: a fast identification of acetylcholinesterase inhibitors from galbanum( ). Phytochem Anal., 24(4):395-400. doi: 10.1002/pca.2422.


Ebrahimzadeh MA, Nabavi SM, Nabavi SF, Dehpour AA. (2011). Anti-oxidant activity of hydroalcholic extract of Ferula gummosa Boiss roots. Eur Rev Med Pharmacol Sci, 15(6):658-64.


Gharaei R, Akrami H, Heidari S, Asadib MH, Jalilic A. (2013). The suppression effect of Ferula gummosa Boiss. extracts on cell proliferation through apoptosis induction in gastric cancer cell line. European Journal of Integrative Medicine, 5(3):241-247.

ABC, Anti-cancer, Anti-metastatic, apoptosis, apoptosis induction, Breast cancer, CDK2, Chapter 7 Isolates and Cancer Research, Cytostatic, G1, G2/M, KIP1, lymphangiogenesis inhibitors, Nausea and Vomiting, p27, PARP, Prostate cancer, S, Sarcoma, TIMP-2

Dehydrocostus (See also costunolide)

Cancers: Breast, cervical., lung, prostate, sarcoma

Action: Anti-metastatic, cytostatic, lymphangiogenesis inhibitors

Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer. Previous studies have shown that S. lappa also induces G2 growth arrest and apoptosis in gastric cancer cells.

Prostate Cancer

The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated. DU145 and TRAMP-C2 cells were cultured in the presence of 0-4 µg/mL HESL with or without 10 ng/mL epidermal growth factor (EGF).

The active compound, dehydrocostus lactone (DHCL), in fraction 7, dose-dependently inhibited the basal and EGF-induced migration of prostate cancer cells. HESL and DHCL reduced matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 secretion but increased TIMP-2 levels in both the absence and presence of EGF.

Results demonstrated that the inhibition of MMP-9 secretion, and the stimulation of TIMP-2 secretion, contribute to reduced migration of DU145 cells treated with HESL and DHCL. This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent in the treatment of prostate cancer (Kim et al., 2012).

Sarcoma

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. The effects of the costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, were studied on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Both compounds inhibited cell viability dose- and time-dependently.

IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase.

These data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2012).

The effects of the sesquiterpene lactones, costunolide and dehydrocostus, on the cell-cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner.

Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27 (Kip1).

In the presence of costunolide, MMP-2 and MMP-9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and MMP-9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock insert system (Lohberger et al., 2013).

Breast Cancer

Several Chinese herbs, namely, pu gong ying (Taraxacum officinale), gan cao (Glycyrrhizae uralensis), chai hu (Bupleurum chinense), mu xiang (Auklandia lappa), gua lou (Trichosanthes kirilowii) and huang yao zi (Dioscoreae bulbiferae), are frequently used in complex traditional Chinese medicine formulas, for breast hyperplasia and breast tumor therapy. The effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. However, the chemical profiles of anti-breast cancer constituents in these herbs have not been investigated thus far.

Two potential anti-breast cancer compounds, costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in mu xiang. The combination of the two compounds showed a synergistic effect on inhibiting the proliferation of MCF-7 cells in vitro, exhibiting potential application in the treatment of breast cancer (Peng, Wang, Gu, Wen & Yan, 2013).

Lymphangiogenesis Inhibitors

In this study, we investigated lymphangiogenesis inhibitors from crude drugs used in Japan and Korea. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro. These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong, 2013).

References

Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biological & Pharmaceutical Bulletin, 36(1), 152-7.


Kim EJ, Hong JE, Lim SS, et al. (2012). The hexane extract of Saussurea lappa and its active principle, dehydrocostus lactone, inhibit prostate cancer cell migration. Journal of Medicinal Food, 15(1), 24-32. doi: 10.1089/jmf.2011.1735.


Kretschmer N, Rinner B, Stuendl N, et al. (2012). Effect of costunolide and dehydrocostus lactone on cell-cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta Medica, 78(16), 1749-1756. doi: 10.1055/s-0032-1315385.


Lohberger B, Rinner B, Stuendl N, et al. (2013). Sesquiterpene lactones downregulate g2/m cell-cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. PLoS One, 8(6), e66300. doi: 10.1371/journal.pone.0066300.


Peng ZX, Wang Y, Gu X, Wen YY, Yan C. (2013). A platform for fast screening potential anti-breast cancer compounds in traditional Chinese medicines. Biomedical Chromatography. doi: 10.1002/bmc.2990.

Anti-cancer, anti-inflammatory, apoptosis, apoptosis induction, AR, blood sugar regulation, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DU145, HT-29, Caco-2, LNCaP and DU145, metastasis, Prostate cancer, S, Vaccinium arctostaphylos

Blueberin

Cancer: Colon, prostate, cervical., breast

Action: Anti-inflammatory, blood sugar regulation

Blueberin is isolated from Vaccinium arctostaphylos (L.).

Colon Cancer

Research has shown that diets rich in phenolic compounds such as those associated with blueberries such as blueberin may be associated with lower risks of several chronic diseases including cancer.

To probe this effect, the bioactivities of various components of blueberries were investigated and their potential anti-proliferation and apoptosis induction effects were investigated using two colon cancer cell lines, HT-29 and Caco-2. Polyphenols in three blueberry cultivars, Briteblue, Tifblue, and Powderblue, were extracted and freeze-dried. The extracts were further separated into phenolic acids, tannins, flavonols, and anthocyanins using an HLB cartridge and LH20 column. The phenolic acid fraction showed relatively lower bioactivities with 50% inhibition at 1000 µg/mL. The greatest anti-proliferation effect among all four fractions was from the anthocyanin fractions. Both HT-29 and Caco-2 cell growth was significantly inhibited by >50% by the anthocyanin fractions at concentrations of 15−50 µg/mL. Anthocyanin fractions also resulted in 2−7 times increase in DNA fragmentation, indicating the induction of apoptosis. The effective dosage levels are close to the reported range of anthocyanin concentrations in rat plasma. These findings suggest that blueberry intake may reduce colon cancer risk (Yi, 2005).

Prostate Cancer; AR+, AR-

The role of polyphenol fractions from both wild and cultivated blueberry fruit was probed in the inhibitory effects on the proliferation of LNCaP, an androgen-sensitive prostate cancer cell line, and DU145, a more aggressive androgen insensitive prostate cancer cell line. When 20µg/ml of a wild blueberry polyphenol fraction was added to LNCaP media, growth was inhibited to 11% of control with an IC50 of 13.3µg/ml. Two similar polyphenol-rich fractions from cultivated blueberries at the same concentration inhibited LNCaP growth to 57% and 26% of control with an IC50 of 22.7 and 5.8µg/ml, respectively. Differences in cell growth inhibition of LNCaP and DU145 cell lines by blueberry fractions rich in polyphenols indicate that blueberry proanthocyanidins have an effect primarily on androgen-dependent growth of prostate cancer cells. Possible molecular mechanisms for growth inhibition are reviewed (Schmidt, 2006).

Prostate Cancer

The mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) down-regulate matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells were investigated. Regulation of MMPs is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. Findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells (Matchett, 2005).

Cervical Cancer, Breast Cancer

Blueberin, extracted with hexane, 50% hexane/ethyl acetate, ethyl acetate, ethanol, and 70% acetone/water at ambient temperature was tested for in vitro anti-cancer activity on cervical and breast cancer cell lines. Ethanol extracts strongly inhibited CaSki and SiHa cervical cancer cell lines and MCF-7 and T47-D breast cancer cell lines. An unfractionated aqueous extract of raspberry and the ethanol extract of blueberry significantly inhibited mutagenesis by both direct-acting and metabolically activated carcinogens (Wedge et al., 2001).

Anti-inflammatory

The reduction of fasting glucose was correlated with the reduction of serum CRP in the Blueberin group whereas in the Placebo group CRP levels were not significantly reduced. Furthermore, the Blueberin also significantly reduced the levels of plasma enzymes ALT, AST and GGT, indicating that, in addition to anti-diabetes effects, the Blueberin also possess pharmacologically relevant anti-inflammatory properties (Abidov et al., 2006).

References

Abidov M, Ramazanov A, Jimenez Del Rio M, Chkhikvishvili I. (2006). Effect of Blueberin on fasting glucose, C-reactive protein and plasma aminotransferases, in female volunteers with diabetes type 2: double-blind, placebo controlled clinical study. Georgian Med News, (141):66-72.

Matchett MD, MacKinnon, L, Sweeney MI, Gottschall-Pass KT, Hurta, RAR. (2006). Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events. The Journal of Nutritional Biochemistry. doi: 10.1016/j.jnutbio.2005.05.014.

Schmidt BM, Erdman Jr JW, Lila MA. (2006). Differential effects of blueberry proanthocyanidins on androgen sensitive and insensitive human prostate cancer cell lines. Cancer Letters, 231(2):240-246. doi: 10.1021/jf049238n.

Wedge DE, Meepagala KM, Magee JB, et al. (2001). Anti-carcinogenic Activity of Strawberry, Blueberry, and Raspberry Extracts to Breast and Cervical Cancer Cells. Journal of Medicinal Food, 4(1):49-51. doi: 10.1089/10966200152053703.

Yi W, Fischer J, Krewer G, Akoh C. (2005). Phenolic Compounds from Blueberries Can Inhibit Colon Cancer Cell Proliferation and Induce Apoptosis. J. Agric. Food Chem, 53(18):7320–7329. doi: 10.1021/jf051333o.

A375 and Hs294, A431, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, anti-oxidative, anti-proliferative, anti-proliferative effect, apoptosis, apoptosis induction, Apoptotic, Autophagy, BAX, Bcl-2, Bcl-xL, BCRP/ABCG2, Berberis amurensis, BIU-87 and T24, Breast cancer, Breast cancer cell lines, CDK, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-preventive agent, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, cytotoxic, Diarrhea or Constipation, ER, ER-negative, ER-positive, FAK, G0/G1, G1, growth-inhibitory, hepato-protective, HIF, HL-60, inflammation, Leukemia, Liver cancer, LNCaP, DU145, PC-3, Lymphoma, MCF-7, MCF-7, MDA-MB-231, Melanoma, metastasis, Nitric Oxide, OVCAR-3, SKOV-3, PARP, PC3, PGE2, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, SiHa and CaSki, Skin cancer, T98G, type, u-PA, VEGF, VEGF

Berberine

Cancer:
Liver,leukemia, breast, prostate, epidermoid (squamous-cell carcinoma), cervical.,testicular, melanoma, lymphoma, hepatoma

Action: Radio-sensitizer, anti-inflammatory, cell-cycle arrest, angiogenesis, chemo-enhancing, anti-metastatic, anti-oxidative

Berberine is a major phytochemical component of the roots and bark of herbal plants such as Berberis, Hydrastis canadensis and Coptis chinensis. It has been implicated in the cytotoxic effects on multiple cancer cell lines.

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et Zucc.), a widely prescribed Chinese herb (Chen et al., 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al., 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al., 2011; Ji, 2011). Berberine has been used in the treatment of diarrhea, neurasthenia, arrhythmia, diabetes, and so forth (Ji, 2011).

Angiogenesis, Chemo-enhancing

Inhibition of tumor invasion and metastasis is an important aspect of berberine's anti-cancer activities (Tang et al., 2009; Ho et al., 2009). A few studies have reported berberine's inhibition of tumor angiogenesis (Jie et al., 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al., 2008; Hur et al., 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al., 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al., 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al., 2009), and caspases (Eom et al., 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al., 2009; Eom et al., 2010). Interestingly, these effects might be specific for cancer cells (Sun et al., 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumorigenesis and tumor progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al., 2009; Tan et al., 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al., 2009; Eom et al., 2010; Burgeiro et al., 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al., 1990; Eom et al., 2010) and autophagy (Wang et al., 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al., 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al., 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicate that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential., and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential., release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether it affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines, and the up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Breast Cancer Metastasis

Berberine also inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicine treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis (Kim, 2010).

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration using melanoma cell lines A375 and Hs294 were probed in an in vitro cell migration assay, indicating that over- expression of cyclo-oxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up- stream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kB, inhibited cell migration. Together, these results indicate that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors (Sing, 2011).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G(1) arrest. G(0)/G(1) phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins.

Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway.

Together, these results indicate berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal., Singh, & Deshwal., 2013).

Anti-oxidative; Breast, Liver and Colon Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined.

Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyperactivation. Both berberine chloride and barberry ethanolic extract were shown to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanolic extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al., 2013).

Source:

Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/485042

References

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Chang KSS, Gao C, Wang LC. (1990). Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Letters, 55(2):103–108.


Chen J, ZHao H, Wang X, et al. (2008). Analysis of major alkaloids in Rhizoma coptidis by capillary electrophoresis-electrospray-time of flight mass spectrometry with different background electrolytes. Electrophoresis, 29(10):2135–2147.


Eom KS, Kim HJ, So HS, et al. (2010). Berberine-induced apoptosis in human glioblastoma T98G Cells Is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. Biological and Pharmaceutical Bulletin, 33(10):1644–1649.


El-Wahab AEA, Ghareeb DA, et al. (2013). In vitro biological assessment of berberis vulgaris and its active constituent, berberine: anti-oxidants, anti-acetylcholinesterase, anti-diabetic and anti-cancer effects. BMC Complementary and Alternative Medicine, 13:218 doi:10.1186/1472-6882-13-218


Hamsa TP & Kuttan G. (2011). Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytotherapy Research, 26(4):568–578.


Hamsa TP & Kuttan G. (2012). Anti-angiogenic activity of berberine is mediated through the down-regulation of hypoxia-inducible factor-1, VEGF, and pro-inflammatory mediators. Drug and Chemical Toxicology, 35(1):57–70.


Han J, Lin H, Huang W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor, 17(7):RA164–RA167.


Ho YT, Yang JS, Li TC, et al. (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Letters, 279(2):155–162.


Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. (2009). The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry, 107(5):955–964.


Islam MM & Kumar GS. (2009). RNA-binding potential of protoberberine alkaloids: spectroscopic and calorimetric studies on the binding of berberine, palmatine, and coralyne to protonated RNA structures. DNA and Cell Biology, 28(12):637–650.


Ji JB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application, People's Medical Publishing House Cp., LTD.


Jie S, Li H, Tian Y, et al. (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. Journal of Gastroenterology and Hepatology, 26(1):179–185.


Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-regulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis, 26(11):1934-1939. doi:10.1093/carcin/bgi154


Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Phytomedicine, 17(6):436-40. doi: 10.1016/j.phymed.2009.08.012.


Komal Singh M, & Deshwal VK. (2013). Natural plant product berberine/cisplatin based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer. Global Journal of Research on Medicinal Plants and Indigenous Medicine, 2(5), 278-291.


Kulkarni SK & Dhir A. (2010). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research, 24(3):317–324.


Lau CW, X. Q. Yao XQ, et al. (2001). Cardiovascular actions of berberine. Cardiovascular Drug Reviews, 19(3):234–244.


Li, XL Hu XJ, Wang H, et al. (2012). Molecular spectroscopy evidence for berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 13(3):873–880.


Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol, 31(1-2):65-9.


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine, a natural product, induces G1-phase cell-cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther, 5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 27(10):2018-27. doi: 10.1093/carcin/bgl043


Meeran SM, Katiyar S & Katiyar SK. (2008). Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicology and Applied Pharmacology, 229(1):33-43. doi:10.1016/j.taap.2007.12.027


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Youn MJ, So HS, Cho HJ, et al. (2008). Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological and Pharmaceutical Bulletin, 31(5):789–795.


Yu HH, Kim KJ, Cha JD, et al. (2005). Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Journal of Medicinal Food, 8(4):454–461.

Anti-cancer, apoptosis, apoptosis induction, Apoptotic, BAX, Bcl-2, Boswellia carterri Birdw, Boswellia serrata, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, DR5, G1, Gastric cancer or Stomach cancer, HT-29, induces apoptosis, LNCaP, PC-3, p21, p53, PARP, Prostate cancer, SGC-7901, MKN-45

Acetyl-keto-beta-boswellic acid (AKBA)

Cancer: Colorectal, prostate, gastric

Action: Anti-cancer

Apoptotic

Acetyl-keto-beta-boswellic acid (AKBA), a triterpenoid isolated from Boswellia carterri Birdw and Boswellia serrata, has been found to inhibit tumor cell growth and to induce apoptosis. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation, and independent of Fas/Fas ligand interaction in colon cancer HT-29 cells (Liu et al., 2002).

Colon Cancer

Although there is increasing evidence showing that boswellic acid might be a potential anti-cancer agent, the mechanisms involved in its action are unclear. It has been shown that acetyl-keto-beta-boswellic acid (AKBA) inhibits cellular growth in several colon cancer cell lines. Cell cycle analysis by flow cytometry showed that cells were arrested at the G1 phase after AKBA treatment.

These results demonstrate that AKBA inhibits cellular growth in colon cancer cells. These findings may have implications for the use of boswellic acids as potential anti-cancer agents in colon cancer (Liu et al., 2006).

AKBA significantly inhibited human colon adenocarcinoma growth, showing arrest of the cell-cycle in G1-phase and induction of apoptosis. AKBA administration in mice effectively delayed the growth of HT-29 xenografts without signs of toxicity (Yuan et al., 2013).

Gastric Cancer

AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited gastric cancer cells line SGC-7901 and MKN-45 xenografts without toxicity.

This effect might be associated with its roles in cell-cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Upon AKBA treatment, β-catenin expression in nuclei was inhibited, and membrane β-catenin was activated (Zhang et al., 2013).

Prostate

The apoptotic effects and the mechanisms of action of AKBA were studied in LNCaP and PC-3 human prostate cancer cells. AKBA induced apoptosis in both cell lines at concentrations above 10 microg/mL. AKBA-induced apoptosis was correlated with the activation of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase (PARP) cleavage.

AKBA treatment increased the levels of CAAT/enhancer binding protein homologous protein (CHOP) and activated a DR5 promoter reporter but did not activate a DR5 promoter reporter with the mutant CHOP binding site. These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP (Lu et al., 2008).

References

Liu J-J, Nilsson A, Oredsson S, et al. (2002). Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis. 23(12): 2087–2093. doi:10.1093/carcin/23.12.2087.

 

 

Liu JJ, Huang B, Hooi SC. (2006). Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br J Pharmacol, 148(8):1099-107.

 

Lu M, Xia L, Hua H, Jing Y. (2008). Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res, 68(4):1180-6. doi: 10.1158/0008-5472.CAN-07-2978.

 

Yuan Y, Cui SX, Wang Y, et al. (2013). Acetyl-11-keto-beta-boswellic acid (AKBA) prevents human colonic adenocarcinoma growth through modulation of multiple signaling pathways. Biochim Biophys Acta, 1830(10):4907-16. doi: 10.1016/j.bbagen.2013.06.039.

 

Zhang YS, Xie JZ, Zhong JL, et al. (2013) Acetyl-11-keto-β-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/β -catenin signaling pathway. Biochim Biophys Acta, 1830(6):3604-15. doi: 10.1016/j.bbagen.2013.03.003.

ABC, anti-apoptotic, Anti-cancer, anti-oxidant, anti-proliferative, anti-tumor, anti-tumor activity, apoptosis, apoptosis induction, apoptosis-inducing, apoptosis-triggering, Apoptotic, BAX, Bcl-2, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemoprevention, Chemotherapy, cytotoxic, induces apoptosis, inhibits proliferation, Leukemia, MDR, Melanoma, Multi-Drug Resistance, Oral cancer, P-gp, Pro-apoptotic, ROS, S, Squamous cell carcinoma

Chelerythrine, Chelidonine and Sanguinarine

Cancer:
Leukemia, oral squamous cell carcinoma, melanoma

Action: Cytotoxic, MDR, apoptosis-triggering, inhibits proliferation

Sanguinarine, chelerythrine and chelidonine are isoquinoline alkaloids derived from the greater celandine. They possess a broad spectrum of pharmacological activities. It has been shown that their anti-tumor activity is mediated via different mechanisms, which can be promising targets for anti-cancer therapy. This study focuses on the differential effects of these alkaloids upon cell viability, DNA damage, and nucleus integrity in mouse primary spleen and lymphocytic leukemic cells, L1210.

Data suggests that cytotoxic and DNA-damaging effects of chelerythrine and sanguinarine are more selective against mouse leukemic cells and primary mouse spleen cells, whereas chelidonine blocks proliferation of L1210 cells. The action of chelidonine on normal and tumor cells requires further investigation (Kaminsky, Lin, Filyak, & Stoika, 2008).

MDR

Cancer cells often develop multi-drug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine, an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects.

Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug, modifying enzymes CYP3A4 and GST in a dose-dependent manner. The expression analysis identified a common set of regulated genes related to apoptosis, cell-cycle, and drug metabolism.

Results suggest that chelidonine is a promising compound for overcoming MDR and enhancing cytotoxicity of chemotherapeutics, especially against leukemia cells. Its efficacy needs to be confirmed in animal models (El-Readi, Eid, Ashour, Tahrani & Wink, 2013).

Induces Apoptosis, Leukemia

Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. This study found that sanguinarine and chelerythrine induced apoptosis in human CEM T-leukemia cells, accompanied by an early increase in cytosolic cytochrome C that precedes caspases-8, -9 and -3 processing. Effects of sanguinarine and chelerythrine on mitochondria were confirmed by clear changes in morphology (3h), howerver chelidonine did not affect mitochondrial integrity. Sanguinarine and chelerythrine also caused marked DNA damage in cells after 1h, but a more significant increase in impaired cells occurred after 6h. Chelidonine induced intensive DNA damage in 15–20% cells after 24h.

Results demonstrated that rapid cytochrome C release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8 (Kaminskyy, Kulachkovskyy, & Stoika, 2008).

Induces Apoptosis

Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. Chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria (Funakoshi et al., 2011).

Oral Cancer, Inhibits cell proliferation

The effects of benzo[c] phenanthridine alkaloids (QBA), known mainly as sanguinarine and chelerythrine, on the inhibition of some kinds of cancer cell proliferation have been established. Sanguinarine is a potential inhibitor of tumorigenesis which suggests that it may be valuable in the development of new anti-cancer drugs for the treatment of oral squamous cell carcinoma (OSCC) (Tsukamoto et al., 2011).

Apoptotic Effects; Melanoma

Mixtures of isoquinoline alkaloids containing protopine, chelidonine, sanguinarine, allocryptopine, and stylopine were applied to murine fibroblast NIH/3T3, mouse melanoma B16F10, and human breast cancer MCF7 cell cultures for 20 and 40 min, and the content of alkaloids in the cell media was measured by capillary electrophoresis (CE). CE separation of isoquinoline alkaloids was performed in 30 mM phosphate buffer (pH 2.5). As these alkaloids have native fluorescence, they were directly detected using the commercially available UV light-emitting diode without fluorescent derivatization. The results showed a differential ability of celandine alkaloids to penetrate into the normal and cancer cell interior, which was inversely proportional to their cytotoxic activity.

While the most effective transport of celandine alkaloids from the cell medium to the cell interior was observed for normal murine fibroblast NIH/3T3 cells (about 55% of total content), cytotoxicity tests demonstrated selective and profound apoptotic effects of a five-alkaloid combination in the mouse melanoma B16F10 cell line (Kulp & Bragina, 2013).

Leukemia

The methanol extract isolated from the greater celandine Chelidonium majus L. (CME) has a strong anti-oxidant potential and exerted the anti-proliferative activity via apoptosis on leukemia cells. CME, due to the presence of the isoquinoline alkaloids and the flavonoid components may play an important role in both cancer chemoprevention through its anti-oxidant activity and modern cancer chemotherapy as a cytotoxic and apoptosis-inducing agent (Nadova et al., 2008).

Apoptosis-inducing Activity

Apoptogenic and DNA-damaging effects of chelidonine (CHE) and sanguinarine (SAN), two structurally related benzophenanthridine alkaloids isolated from Chelidonium majus L. (Papaveraceae), were compared. Both alkaloids induced apoptosis in human acute T-lymphoblastic leukaemia MT-4 cells. Apoptosis induction by CHE and SAN in these cells was accompanied by caspase-9 and -3 activation and an increase in the pro-apoptotic Bax protein. An elevation in the percentage of MT-4 cells possessing caspase-3 in active form after their treatment with CHE or SAN was in parallel to a corresponding increase in the fraction of apoptotic cells. CHE, in contrast to SAN, does not interact directly with DNA.

This fact is in line with DNA-damaging effects of the alkaloids detected in the COMET assay. Nevertheless, apoptosis-inducing activity of CHE even slightly exceeded that of SAN (Philchenkov et al., 2008).

Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain. Apart from sanguinarine and chelerythrine, chelidonine turned out to be a potent inducer of apoptosis, triggering cell death at concentrations of 0.001 mM, while protopine and allocryptopine were less effective. Similar to Ukrain, apoptosis signaling of chelidonine involved Bcl-2 controlled mitochondrial alterations and caspase-activation (Habermehl et al., 2006).

References

El-Readi MZ, Eid S, Ashour ML, Tahrani A, & Wink M. (2013). Modulation of Multi-drug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids. Phytomedicine, 20(3-4), 282-94. doi: 10.1016/j.phymed.2012.11.005.


Funakoshi T, Aki T, Nakayama H, et al. (2011). Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine. Toxicol In Vitro, 25(8):1581-7. doi: 10.1016/j.tiv.2011.05.028.


Habermehl D, Kammerer B, Handrick R, et al. (2006). Pro-apoptotic activity of Ukrain is based on Chelidonium majus L. alkaloids and mediated via a mitochondrial death pathway. BMC Cancer, 6:14.


Kaminskyy V, Lin KW, Filyak Y, & Stoika R. (2008). Differential effect of sanguinarine, chelerythrine and chelidonine on DNA damage and cell viability in primary mouse spleen cells and mouse leukemic cells. Cell Biology International., 32(2), 271-277.


Kaminskyy V, Kulachkovskyy O,Stoika R. (2008). A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicology Letters, 177(3), 168-81. doi: 10.1016/j.toxlet.2008.01.009.


Kulp M, Bragina O. (2013). Capillary electrophoretic study of the synergistic biological effects of alkaloids from Chelidonium majus L. in normal and cancer cells. Analytical and Bioanalytical Chemistry, 405(10), 3391-7. doi: 10.1007/s00216-013-6755-y.


Nadova S, Miadokova E, Alfoldiova L, et al. (2008). Potential anti-oxidant activity, cytotoxic and apoptosis-inducing effects of Chelidonium majus L. extract on leukemia cells. Neuro Endocrinol Lett, 29(5):649-52.


Philchenkov A., Kaminskyy V., Zavelevich M., Stoika R. (2008). Apoptogenic activity of two benzophenanthridine alkaloids from Chelidonium majus L. does not correlate with their DNA-damaging effects. Toxicology In Vitro, 22(2), 287-95.


Tsukamoto H, Kondo S, Mukudai Y, et al., (2011). Evaluation of anti-cancer activities of benzo[c]phenanthridine alkaloid sanguinarine in oral squamous cell carcinoma cell line. Anti-cancer Res, 31(9):2841-6.


Zhe C, Li-Juan W, Ming Hui W, et al. (2011). Mechanism governing reversal of Multi-drug resistance in human breast carcinoma cells by chelerythrine. Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 33(1):45-50. doi: 10.3881/j.issn.1000-503X.2011.01.010.

ABC, Anti-cancer, anti-inflammatory, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, apoptosis, apoptosis induction, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Bladder cancer, Breast cancer, c-Fos, c-Jun, CDC2, CDC25A, CDC25C, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, ERK1, G1, G2/M, hTERT, JNK, Lung cancer, lymphangiogenesis inhibitor, lymphangiogenesis inhibitors, MCF-7, MCF-7, MDA-MB-231, MDA-MB-231, MDR, metastasis, MPSC1 (PT), A2780 (PT) and SKOV3 (PT), Nausea and Vomiting, NFATc1, Ovarian cancer, p21, p38, p53, PARP, Pro-apoptotic, pro-oxidative, Prostate cancer, ROS, S, Sarcoma, T24, TIMP-2, TNF

Costunolide and Dehydrocostus Lactone

Cancers:
Breast, cervical., lung, ovarian, bladder, leukemia, prostate, gastric

Action: Anti-inflammatory, pro-oxidative, MDR, lymphangiogenesis inhibitor, anti-metastasis, mediates apoptosis, anti-metastatic

Components of Saussurea lappa Clarke, Vladimiria souliei (Franchet) Lingelsheim (Compositae)

Breast cancer; Anti-metastatic

It was found that costunolide inhibited the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. The expression of hTERT mRNA was also inhibited but hTR mRNA was not. In addition, the bindings of transcription factors in hTERT promoters were significantly decreased in both cells by the treatment of costunolide. These results suggest that costunolide inhibited the growth of both MCF-7 and MDA-MB-231 cells and this effect was mediated at least in part by a significant reduction in telomerase activity (Choi et al., 2005).

Breast Cancer

Costunolide has been demonstrated to suppress tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNF-α induced NF-kB activation. Costunolide also inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays.

In addition, costunolide inhibited in vitro TNF-α induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNF-α induced NF-kB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-kB-dependent gene to mediate breast cancer cell growth and metastases. Taken together, these results suggest that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNF-α induced NF-k B activation, suggesting that costunolide as well as SLC may be promising anti-cancer drugs, especially for metastatic breast cancer (Choi et al., 2013).

Several Chinese herbs, namely, Herba Taraxaci Mongolici (Pu Gong Ying), Radix Glycyrrhizae Uralensis (Gan Cao), Radix Bupleuri (Chai Hu), Radix Aucklandiae Lappae/ Radix Aucklandiae Lappae (Mu Xiang), Fructus Trichosanthis (Gua Lou) and Rhizoma Dioscoreae Bulbiferae (Huang Yao Zi) are frequently used in complex traditional Chinese medicine formulas for breast hyperplasia and breast tumor therapy.

The pharmacological effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. A bioactivity-oriented screening platform, which was based on a human breast cancer MCF-7 cellular model was developed to rapidly screen the 6 Chinese herbs. Two potential anti-breast cancer compounds, which were costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in Radix Aucklandiae Lappae.

Combination of the two compounds showed a synergism on inhibiting the proliferation of MCF-7 cells in vitro, which exhibits a potential application prospect for breast cancer therapy. This bioactivity-oriented screening strategy is rapid, economical., reliable and specific for screening potential anti-breast cancer compounds in traditional Chinese medicines (Peng et al., 2013).

Dehydrocostuslactone (DHE) suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell-cycle progression and cell death through SOCS-1 and SOCS-3.

Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer (Kuo et al., 2009).

ER- Breast Cancer

Costunolide induced apoptosis through the extrinsic pathway, including the activation of Fas, caspase-8, caspase-3, and degradation of PARP. However, it did not have the same effect on the intrinsic pathway as revealed by analysis of mitochondrial membrane potential (Δψ m) with JC-1 dye and expression of Bcl2 and Bax proteins level.

Furthermore, costunolide induced cell-cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression, independent of p53 pathway in p53-mutant MDA-MB-231 cells, and increases Cdc2-p21WAF1 binding/

Through this study it was confirmed that costunolide induces G2/M cell-cycle arrest and apoptotic cell death via extrinsic pathway in MDA-MB-231 cells, suggesting that it could be a promising anti-cancer drug especially for ER negative breast cancer (Choi et al., 2012).

Bladder Cancer

Costunolide, a member of sesquiterpene lactone family, possesses potent anti-cancer properties. The effects of costunolide were investigated on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis, which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Δψm).

These effects were significantly blocked when the cells were pre-treated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, and of   survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer (Rasul et al., 2013).

Sarcomas; MDR

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment.

The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction.

These data demonstrate that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2013).

Leukemia, Lung Cancer

Costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, has been found to induce apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. Mitogen-activated protein kinases (MAPKs) were investigated for their involvement in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells.

Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 minutes of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis.

Furthermore, pre-treatment with the anti-oxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 days) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model (Choi et al., 2009).

Prostate Cancer

Several pharmacological and biochemical assays were used to characterize the apoptotic-signaling pathways of costunolide in prostate cancer cells. Costunolide showed effective anti-proliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC¨) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca(2+), DNA damage response and ATR phosphorylation.

This indicated the crucial role of intracellular Ca(2+) mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling. Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca(2+) that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell-cycle and subsequent apoptotic cell death in human prostate cancer cells (Hsu et al., 2011).

Gastric Cancer, Prostate Cancer

Radix Aucklandiae Lappae/Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer; previous studies have shown that S. lappa also induces G(2) growth arrest and apoptosis in gastric cancer cells. The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated.

The active compound, dehydrocostus lactone (DHCL), in fraction 7 dose-dependently inhibited the basal and EGF-induced migration of prostate cancer cells. HESL and DHCL reduced matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 secretion but increased TIMP-2 levels in both the absence and presence of EGF. These results demonstrate that the inhibition of MMP-9 secretion and the stimulation of TIMP-2 secretion contribute to reduced migration of DU145 cells treated with HESL and DHCL.

This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent for the treatment of prostate cancer (Kim et al., 2012).

Anti-metastatic

Lymphangiogenesis inhibitors from crude drugs used in Japan and Korea were investigated for their impact on metastasis. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro.

Among isolated compounds, several compounds; costunolide, dehydrocostus lactone, psoracorylifol D, bavachinin, bakuchiol, showed an inhibitory effect on the proliferation and the capillary-like tube formation of TR-LE cells. In addition, all compounds showed selective inhibition of the proliferation of TR-LE cells compared to Hela and Lewis lung carcinoma (LLC) cells.

These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong et al., 2013).

Ovarian Cancer, MDR

The apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, was studied in platinum-resistant human ovarian cancer cells relative to cisplatin.

The MTT assay for cell viability, PI staining for cell-cycle profiling, and annexin V assay for apoptosis analysis were performed. Costunolide induced apoptosis of platinum-resistant cells in a time and dose-dependent manner and suppressed tumor growth in the SKOV3 (PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, caspase-8, and caspase-9. Pre-treatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

Data suggests that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancers (Yang, Kim, Lee, & Choi, 2011).

Anti-inflammatory, Anti-oxidant, Mediates Apoptosis

Cheon et al. (2013) found that costunolide significantly inhibited RANKL-induced BMM differentiation into osteoclasts in a dose-dependent manner without causing cytotoxicity. Costunolide did not regulate the early signaling pathways of RANKL, including the mitogen-activated protein kinase and NF-κB pathways.

However, costunolide suppressed nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression via inhibition of c-Fos transcriptional activity without affecting RANKL-induced c-Fos expression. The inhibitory effects of costunolide were rescued by overexpression of constitutively active (CA)-NFATc1. Taken together, these results suggest that costunolide inhibited RANKL-induced osteoclast differentiation by suppressing RANKL-mediated c-Fos transcriptional activity.

References

Cheon YH, Song MJ, Kim JY, Kwak SC, Park JH, Lee CH, Kim JJ, Kim JY, Choi MK, Oh J, Kim YC, Yoon KH., Kwak HB, Lee MS. (2013). Costunolide inhibits osteoclast differentiation by suppressing c-Fos transcriptional activity. Phytotherapy, July, (6). doi: 10.1002/ptr.5034.

Choi SH, Im E, Kang HK, et al. (2005). Inhibitory effects of costunolide on the telomerase activity in human breast carcinoma cells. Cancer Lett, 227(2):153-62.


Choi JH, Lee KT. (2009). Costunolide-induced apoptosis in human leukemia cells: involvement of c-jun N-terminal kinase activation. Biol Pharm Bull, 32(10):1803-8.


Choi YK, Seo HS, Choi HS, et al. (2012). Induction of Fas-mediated extrinsic apoptosis, p21WAF1-related G2/M cell-cycle arrest and ROS generation by costunolide in estrogen receptor-negative breast cancer cells, MDA-MB-231. Mol Cell Biochem, 363(1-2):119-28. doi: 10.1007/s11010-011-1164-z.


Choi YK, Cho S-G, Woo S-M, et al. (2013). Saussurea lappa Clarke-Derived Costunolide Prevents TNF α-Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF-κ B Activity. Evidence-Based Complementary and Alternative Medicine. doi:10.1155/2013/936257.


Hsu JL, Pan SL, Ho YF, Het al. (2011). Costunolide induces apoptosis through nuclear calcium2+ overload and DNA damage response in human prostate cancer. The Journal of Urology, 185(5):1967-74. doi: 10.1016/j.juro.2010.12.091.


Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biol Pharm Bull, 36(1):152-7.


Kim EJ, Hong JE, Lim SS, et al. (2012). The hexane extract of Saussurea lappa and its active principle, dehydrocostus lactone, inhibit prostate cancer cell migration. J Med Food, 15(1):24-32. doi: 10.1089/jmf.2011.1735.


Kretschmer N, Rinner B, Stuendl N, et al. (2012). Effect of costunolide and dehydrocostus lactone on cell-cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Planta Med, 78(16):1749-56. doi: 10.1055/s-0032-1315385.


Kuo PL, Ni WC, Tsai EM, Hsu YL. (2009). Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Mol Cancer Ther, 8(5):1328-39. doi: 10.1158/1535-7163.MCT-08-0914.


Peng ZX, Wang Y, Gu X, Wen YY, Yan C. (2013). A platform for fast screening potential anti-breast cancer compounds in traditional Chinese medicines. Biomed Chromatogr. doi: 10.1002/bmc.2990.


Rasul A, Bao R, Malhi M, et al. (2013). Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction. Molecules, 18(2):1418-33. doi: 10.3390/molecules18021418.


Yang YI, Kim JH, Lee KT, & Choi JH. (2011). Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species. Gynecologic Oncology, 123(3), 588-96. doi: 10.1016/j.ygyno.2011.08.031.

Akt, Anemarrhena asphodeloides, angiogenesis, Anti-cancer, anti-inflammatory, anti-oxidant, AP-1, apoptosis, apoptosis induction, Breast cancer, Chapter 7 Isolates and Cancer Research, chelating agent, chemo-preventive, Chemo-preventive agent, neuro-protective, Radio-protective, U373

Mangiferin

Cancer: Breast, gliomas, colon

Action: Chemo-preventive agent, chelating agent

Mangiferin, a glucosylxanthone isolated from Anemarrhena asphodeloides, is an efficient iron chelator, therefore preventing the generation of hydroxyl radical in Fenton-type reactions. Numerous published in vitro and in vivo pharmacological studies have demonstrated many other activities of mangiferin: analgesic, anti-diabetic, anti-sclerotic, anti-microbial and anti-viral., cardio-, hepato-, and neuro-protective, anti-inflammatory, anti-allergic, MAO-inhibiting and memory-improving, as well as radio-protective against X-ray, gamma, and UV radiation. Several studies also indicated its ability to inhibit cancerogenesis and cancer cell growth by apoptosis induction in vitro and in vivo (Matkowski et al., 2013).

Colon Cancer; Pre-neoplastic Lesions

Recent studies have shown that mangiferin has potential as an anti-oxidant, and as an anti-viral agent. The effects of mangiferin in rat colon carcinogenesis induced by the chemical carcinogen, azoxymethane (AOM), were studied. Two experiments were carried out: a short-term   assay to investigate the effects of mangiferin on the development of pre-neoplastic lesions by AOM, aberrant crypt foci (ACF); and a long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in a diet significantly inhibited the ACF development in rats treated with AOM, compared to rats treated with AOM alone (64.6±22.0 vs. 108.3±43.0).

In the long-term assay, the group treated with 0.1% mangiferin in initiation phase of the experimental protocol had significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3% and 41.8% reductions of the group treated with AOM alone for incidence and multiplicity, respectively). In addition, the cell proliferation in colonic mucosa was reduced in rats treated with mangiferin (65–85% reductions of the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemo-preventive agent (Yoshimi et al., 2001).

Mangiferin may be used as an effective chemo-preventive agent against breast cancer. Mangiferin, which is a naturally occurring glucosylxanthone, has exhibited promising anti-cancer activities. In this study, the anti-cancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. Li et al. (2013) showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells.

Gliomas

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which play a key role in invasion, migration, and angiogenesis of astrogliomas and other malignant tumors. Thus, controlling MMPs has been considered an important therapeutic strategy for prevention and/or treatment of gliomas.

Mangiferin inhibits the binding of NF- κB and AP-1 to the MMP-9 promoter and suppresses the PMA-induced phosphorylation of Akt and MAP kinases, which are upstream signaling molecules in MMP-9 expression. Thus, the specific inhibition of MMP-9 by mangiferin may provide a valuable pharmacological tool for treatment of gliomas (Jung et al., 2012,).

References

Jung JS, Jung K, Kim DH, Kim HS. (2012). Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3K/Akt and MAPK signaling pathways. Pharmacol Res, 66(1):95-103. doi: 10.1016/j.phrs.2012.02.013.


Li H, Huang J, Yang B, et al. (2013). Mangiferin exerts anti-tumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β -catenin signaling pathway. Toxicol Appl Pharmacol, 272(1):180-90. doi: 10.1016/j.taap.2013.05.011.


Matkowski A, Ku ś P, G-ralska E, Wo ź niak D. (2013). Mangiferin – a bioactive xanthonoid, not only from mango and not just anti-oxidant. Mini Rev Med Chem, 13(3):439-55.


Yoshimi N, Matsunaga K, Katayama M, et al. (2001). The inhibitory effects of mangiferin, a naturally occurring glucosylxanthone, in bowel carcinogenesis of male F344 rats. Cancer Letters, 163(2):163-70. doi:10.1016/S0304-3835(00)00678-9

Anti-cancer, anti-inflammatory, apoptosis, apoptosis induction, Apoptotic, Bcl-2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Glioblastoma, Hep3B and Huh7, MDA-MB-231, Osteosarcoma, p53, Sarcoma, SKOV-3, TfR, tumor apoptosis, various Garcinia species

Gambogic acid

Cancer:
Leukemia, metastatic breast, osteocarcinoma, glioblastoma, breast, lung, liver

Action: Anti-cancer, tumor apoptosis

Gambogic acid (GA) is the principal active ingredient of gamboges which is the resin from various Garcinia species including Garcinia hanburyi (Hook. F.) and Garcinia morella (Panthong et al., 2007). GA is a natural product with potent apoptotic activity. GA has various biological effects, such as anti-inflammatory, analgesic and anti-pyretic as well as anti-cancer activities.

Tumor Apoptosis, Osteocarcinoma, Glioblastoma, Breast, Lung, Liver

GA binding to Transferrin receptor (TfR) induces a unique signal leading to rapid apoptosis of tumor cells. (Kasibhatla et al., 2005; Gu et al., 2008). GA enhances p53 protein level through inhibition of mdm2 oncogene expression and thereby hampers p53 harboring tumor growth. GA could increase the chemotherapeutic effect of cisplatin in human osteosarcoma treatment through inducing the cell-cycle arrest and promoting cell apoptosis (Zhao et al., 2013).

In vitro and in vivo studies have demonstrated its potential as an excellent cytotoxicity against a variety of malignant tumors, including glioblastoma, as well as cancers of the breast, lung and liver. GA is currently investigated in clinical trials in China (Qi et al., 2008).

Leukemia

Gambogic acid (GA) has been found to inhibit the proliferation of Jurkat leukemia cells with 50% inhibitory concentration values of 1.51±0.09 (24 hours), 0.98±0.13 (48 hours), and 0.67±0.12 µmol/L (72 hours). GA was able to induce apoptosis of Jurkat cells. Treated by GA, the expression of DIO-1 was up-regulated, and that of Bcl-2 and NF-κB was down-regulated, leading to the activation of pro-caspase 3. GA induced the translocation of DIO-1 to the nucleus. GA suppressed the proliferation of Jurkat cells by apoptosis induction. DIO-1 triggered early-stage cell death in GA-treated Jurkat cells (Wang et al., 2008).

Metastatic Cancer

Patients with advanced or metastatic cancer who had not received any effective routine conventional treatment, or who had failed to respond to the existing conventional treatment, were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from days 1– 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of 5 times during a 2-week cycle (Group B). The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms.

The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on days 1–5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule (Chi et al., 2013).

References

Chi Y, Zhan XK, Yu H, et al. (2013). An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors. Chin Med J, 126(9):1642-6.


Gu H, Wang X, Rao S, et al. (2008). Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells. Mol Cancer Ther, 7:3298–3305. doi: 10.1158/1535-7163.MCT-08-0212.


Kasibhatla S, Jessen KA, Maliartchouk S, et al. (2005). A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. Proc Natl Acad Sci, 102:12095–12100. doi: 10.1073/pnas.0406731102.


Panthong A, Norkaew P, Kanjanapothi D, et al. (2007). Anti-inflammatory, analgesic and anti-pyretic activities of the extract of gamboge from Garcinia hanburyi Hook f. J Ethnopharmacol, 111:335–340. doi: 10.1016/j.jep.2006.11.038.


Qi Q, Gu H, Yang Y, et al. (2008). Involvement of matrix metalloproteinase 2 and 9 in gambogic acid induced suppression of MDA-MB-435 human breast carcinoma cell lung metastasis. J Mol Med, 86:1367–1377. doi: 10.1007/s00109-008-0398-z.


Wang Y, Chen Y, Chen Z, et al. (2008). Gambogic acid induces death inducer-obliterator 1-mediated apoptosis in Jurkat T cells. Acta Pharmacologica Sinica, 29:349–354. doi:10.1111/j.1745-7254.2008.00762.x.


Zhao W, You CC, Zhuang JP, et al. (2013). Viability inhibition effect of gambogic acid combined with cisplatin on osteosarcoma cells via mitochondria-independent apoptotic pathway. Mol Cell Biochem.