Category Archives: Chapter 7 Isolates and Cancer Research

all, Chapter 7 Isolates and Cancer Research

Acetoside

Cancer: Lung cancer, melanoma

Action: Anti-metastatic

Acetoside is isolated from Stachys sieboldii (Miq), Arctostaphylos uva-ursi [(L.) Spreng, Cistanche deserticola (Ma).

Anti-metastatic; Lung Cancer

The anti-metastatic effect of acteoside, a phenylethanoid glycoside widely distributed in the plant kingdom, was examined with respect to lung metastasis using a mouse model injected with B16 melanoma cells intravenously. Administration of acteoside prolonged survival time significantly and the average survival time was 63.3 +/- 3.4d compared with 52.1 +/- 2.5d in control mice. This result suggests that acteoside showed suppressive effect on lung metastasis of B16 melanoma cells (Ohno et al., 2009).

Melanoma

Acteoside showed an inhibitory effect on tyrosinase activity and melanin synthesis in both cell-free assay systems and cultured B16F10 melanoma cells. Acteoside decreased levels of tyrosinase, tyrosinase-related protein-1 (TRP-1) and microphthalmia-associated transcription factor (MITF) proteins, whereas it increased ERK phosphorylation. Acteoside suppressed melanogenesis induced by α-melanocyte-stimulating hormone and showed UV-absorbing effects (Son et al., 2011). Acteoside also inhibited production of both melanin and cyclic AMP in cells stimulated by 1 micromol/l forskolin, an adenyl cyclase activator. Acteoside showed anti-oxidant activity in a cell-free DPPH (1-diphenyl-2-picrylhydroazyl) assay and inhibited generation of intracellular reactive oxygen species (Song & Sim., 2009).

References

Ohno T, Inoue M, Ogihara Y, Saracoglu I. (2012). Anti-metastatic activity of acteoside, a phenylethanoid glycoside. Biological & Pharmaceutical Bulletin, 25(5):666-8. doi: 10.1248/bpb.25.666


Song HS, Sim SS. (2009). Acteoside inhibits alpha-MSH-induced melanin production in B16 melanoma cells by inactivation of adenyl cyclase. J Pharm Pharmacol, 61(10):1347-51. doi: 10.1211/jpp/61.10.0011.


Son YO, Lee SA, Kim SS, et al. (2011). Acteoside inhibits melanogenesis in B16F10 cells through ERK activation and tyrosinase down-regulation. J Pharm Pharmacol, 63(10):1309-19. doi: 10.1111/j.2042-7158.2011.01335.x.

angiogenesis, bFGF, Chapter 7 Isolates and Cancer Research, Chemotherapy, inflammation, metastasis, Nitric Oxide, radiotherapy, TNF, VEGF, VEGF, VEGFR, VEGFR-2

VEGF

The tumour microenvironment is closely correlated with the malignant degrees, metastasis, and recurrence of tumours. Besides, the acid environment, oxygen deficiency, and other inducible factors may severely affect the efficacies of routine therapies, radiotherapy and chemotherapy. Recent studies have also proved that many Chinese herbs could fight against tumour vascular angiogenesis, lower serum VEGF concentration, and inhibit expressions of VEGF. This may lead to the development of new potential antiangiogenic drugs.

Angiogenesis

Angiogenesis, the sprouting of new capillaries, is required for the development of the vascular system and, consequently, the growth of vertebrates. Angiogenic proteins, including several from the fibroblast growth factor family were found to be mitogenic not only for vascular endothelial cells but also for a wide variety of other types of cells and appeared to promote angiogenesis as part of coordinated tissue growth and repair. In the late 1980s the first selective angiogenic growth factor was purified on the basis of its ability to induce transient vascular leakage and endothelial cell mitogenesis called vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) (Neufeld et al 1994). The identification of VEGF (Ferrara 1993) set the stage for a rapid expansion in the understanding of what now appears to be one of the most important mediators of physiologic and pathologic angiogenesis yet discovered.

Transcription of VEGF mRNA is induced by a variety of factors. Serum-derived and paracrine growth factors and cytokines, including Platelet-Derived Growth Factor BB (PDGF-BB), basic fibroblast growth factor (bFGF) (Sipos et al 2002), epidermal growth factor, tumor necrosis factor α (Frank et al 1995), nitric oxide (Frank et al 1999), transforming growth factor-β1, and interleukin-1β (Li et al 1995; Jung et al 2001), can each induce expression of VEGF from 3- to 20-fold in a variety of cultured cells.

Hypoxia

Without an independent blood supply, tumours must rely on diffusion to obtain oxygen and other nutrients, and typically cannot grow more than 2-3 mm in size. Thus, a growing tumour without sufficient vasculature will have hypoxic areas.

In response to hypoxic conditions, tumours secrete vascular endothelial growth factor (VEGF) in order to recruit new vasculature, which then provides a supply of oxygen (Gimbrone et al., 1972). Hypoxia is known to induce angiogenesis, thereby providing a compensatory mechanism by which tissues can increase oxygenation. Therefore, diminished O2 is one of the most intriguing transcriptional inducers of VEGF (Shweiki et al 1992) and its receptors (Tuder, Flook & Voelkel 1995) in normal and transformed cells. Hypoxic induction of VEGF appears to be a general response since many types of cultured cells have been observed to increase VEGF mRNA levels by approximately 10-50-fold as a consequence of lowering the percentage of O2 from ambient 21% to the range of 0-3% (Sipos et al 2002).

Vascular permeability factor (VPF)

The microvasculature of tumours is hyperpermeable compared with that of most normal tissues and as a consequence, fluid and plasma accumulate in the interstitium of solid tumors (Heldin et al 2004) and this barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition, which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factor in vitro, and it presumably stimulates EC proliferation in vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation (Senger et al 1993; Baban & Seymour 1998). Although VEGF is known to be a powerful growth factor for therapeutic angiogenesis/vascularization in the ischemic hind limb and myocardium, it has other activities that can increase the proliferation and permeability of capillary endothelial cells. These activities may produce unwanted side effects, such as tumor angiogenesis, vascular leakage, oedema, and inflammation (Chae et al, 2000).

Medicinal herbs and their phytochemicals are potential novel leads for developing antiangiogenic drugs. Jeong et al., (2011) conducted a review that aimed to assess the current status of research with medicinal herbs and their phytochemicals for the development of antiangiogenic agents for cancer and other angiogenesis-related diseases including inflammation, diabetic retinopathy, endometriosis and obesity. Most studies reviewed have focused on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR-2) signaling for endothelial response processes and have led to the identification of many potential antiangiogenic agents.

Since human clinical trials with antiangiogenic modalities targeting VEGF/VEGFR-2 signaling have shown limited efficacy and occasional toxic side effects, screening strategies for herbal phytochemicals based on other signaling pathways important for cancer-endothelial and stromal crosstalks should be emphasized in the future.

Reference

Baban DF & Seymour LW. (1998) Control of tumour vascular permeability. Advanced Drug Delivery Reviews. Volume 34, Issue 1, 5 October 1998, Pp 109-9. doi:10.1016/S0169-409X(98)00003-9

Chae JK, Kim I, Lim ST, et al. (2000) Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol. 2000 Dec; 20(12): 2573-8.

Ferrara N. (1993) Trends Cardiovasc. Med. 3, 244–250

Frank S, Stallmeyer B, Kämpfer H, Kolb N, Pfeilschifter J. (1999) Nitric oxide triggers enhanced induction of vascular endothelial growth factor expression in cultured keratinocytes (HaCaT) and during cutaneous wound repair. FASEB J. 1999 Nov;13(14):2002-14.

Heldin C-H, Rubin K, Pietras K & Östman A. High interstitial fluid pressure — an obstacle in cancer therapy. Nature Reviews Cancer 4, 806-813 (October 2004) doi:10.1038/nrc1456

Jung YD, Liu W, Reinmuth N, et al. (2001) Vascular endothelial growth factor is up-regulated by interleukin-1 beta in human vascular smooth muscle cells via the P38 mitogen-activated protein kinase pathway. Angiogenesis. 2001;4(2):155-62.

Li J, Perrella M. A, Tsai J-C, et al. (1995) Induction of Vascular Endothelial Growth Factor Gene Expression by Interleukin-1 in Rat Aortic Smooth Muscle Cells. J. Biol. Chem. 270, 308–312

Neufeld G, Tessler S, Gitay-Goren H, Cohen T & Levi B-Z. (1994) Prog. Growth Factor Res. 5, 89–97

Senger DR, Water L, Lawrence F. Brown LF, et al. (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer and Metastasis Reviews. Volume 12, Numbers 3-4, Pp. 303-24, DOI: 10.1007/BF00665960

Shweiki D, Itin A, Soffer D & Keshet E. (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845

Sipos B, Weber D, Ungefroren H, et al. (2002) Vascular endothelial growth factor mediated angiogenic potential of pancreatic ductal carcinomas enhanced by hypoxia: an in vitro and in vivo study. Int J Cancer. 2002 Dec 20;102(6):592-600.

Tuder RM, Flook BE & Voelkel NF. (1995) J. Clin. Invest. 95, 1798–1807

Jeong SJ, Koh W, Lee EO, et al. (2011) Antiangiogenic phytochemicals and medicinal herbs. Phytother Res. 2011 Jan;25(1):1-10. doi: 10.1002/ptr.3224. DOI: 10.1002/ptr.3224

Cordyceps sinensis

The aqueous extract of Cordyceps sinensis (Cs), one of the traditional Chinese medicines, has been used for the treatment of a wide range of disorders for centuries. It is generally accepted that its cultivated Cs fungi possess the same functions as Cs natural herbs. Although polysaccharide from Cs is one of its bioactive compositions, its antitumor ability has not been confirmed. In a study, Yang et al., (2005) investigated the effects of the exopolysaccharide fraction (EPSF) of a cultivated Cs fungus on c-Myc, c-Fos, and vascular endothelial growth factor (VEGF) expression of tumor-bearing mice. The mice (C57BL/6) were administered three different doses of EPSF peritoneally every 2 days, starting from the day of implantation of B16 melanoma cells through their tail veins for 27 days (14 times).

Sections from mouse paraffin-embedded liver and lung tissues were subjected to immunohistochemical analyses. The results of c-Myc, c-Fos, and VEGF expression were analyzed using SimplePCI image analysis software. The c-Myc, c-Fos, and VEGF levels in the lungs and livers of EPSF-treated mice were found to be significantly lower than those of untreated mice (p<0.05). This suggests that EPSF had inhibited tumor growth in the lungs and livers of mice, and that it might be a potential adjuvant in cancer therapy.

Reference

Yang J, Zhang W, Shi P, Chen J, Han X, Wang Y. (2005) Effects of exopolysaccharide fraction (EPSF) from a cultivated Cordyceps sinensis fungus on c-Myc, c-Fos, and VEGF expression in B16 melanoma-bearing mice.

Pathol Res Pract. 2005;201(11):745-50. Epub 2005 Oct 19.

Ligustrazine

Ligustrazine is isolated from Ligustici Chuangxiong and can significantly inhibit the growth of vascular endothelial cell line (VEC-304), induce VEC-304 apoptosis and down-regulate the expression of VEGF (Peng, Jiang, & Wu, 2006).

Reference

Peng J, Jiang D, & Wu Y. (2006) Effect of Ligustrazine on Apoptosis of Expression of VEGF Gene in Blood Vessel Endothelial Cells. Zhong Hua Shi Yong Zhong Xi Yi Zha Zhi, 19(21), 2562–2564.

Ginsenoside Rg2

Ginseng saponins 20(S)-ginsenoside Rg2 extracted from cultured Panax notoginseng cells in a fermenter show a protection effect on human umbilical cord vein endothelial cells (VEC-304) from H2O2-induced cell apoptosis. When 50 mg/ml 20(S)-ginsenoside Rg2 was present in the culture medium for 8 h, the H2O2-damaged VEC-304 cells acquired about 11-fold ( p < 0.01) on the amount and about 2-fold ( p < 0.05) increase in PA activity compared with those untreated cells. And the Rg2 has a strong ability in scavenging intracellular ROS induced by H2O2 (Xin et al., 2005).

Reference

Xin Xj, Zhong Jj, Wei Dz, Liu Jw. (2005) Protection effect of 20(S)-ginsenoside Rg2 extracted from cultured Panax notoginseng cells on hydrogen peroxide-induced cytotoxity of human umbilical cord vein endothelial cells in vitro. Process Biochemistry 40 (2005) 3202–3205

Anti-cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, Chemoprevention, CSC, CSCs, EMT, Notch

Curcumin and CSCs

Action: Anti-cancer

The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, Sonic Hedgehog) and specific microRNAs involved in acquisition of epithelial–mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments (Li & Zhang, 2014).

Reference

Li Y, Zhang T. (2014) Targeting Cancer Stem Cells by Curcumin and Clinical Applications. Cancer Letters. 23 January 2014

Anti-cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, Chemoprevention, CSC, CSCs, EMT, Notch

Cancer stem cell (CSC)

microRNA

Action: Anti-cancer

The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, Sonic Hedgehog) and specific microRNAs involved in acquisition of epithelial-mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments (Li & Zhang, 2014).

Reference

Li Y, Zhang T. (2014) Targeting Cancer Stem Cells by Curcumin and Clinical Applications. Cancer Letters. 23 January 2014

angiogenesis, Anti-angiogenesis, Chapter 7 Isolates and Cancer Research, HepG2, Torilis japonica

Torilin

Cancer: none noted

Action: Anti-angiogenesis

Torilin is a sesquiterpene compound purified from fruits of Torilis japonica (Umbelliferae).

Torilin decreased both neovascularization and basic fibroblast growth factor-induced vessel formation. Torilin also reduced the proliferation and tube formation of human umbilical vein endothelial cells. In addition, the concentrated conditioned media obtained from torilin-treated HepG2 human hepatoblastoma cells blocked the angiogenic activation of torilin-untreated concentrated conditioned media, indicating that torilin may have an inhibitory effect on tumor-induced angiogenesis.

Torilin significantly down-regulated the expression of hypoxia-inducible vascular endothelial growth factor and insulin-like growth factor-II. Taken together, our data suggest that torilin may be a strong angiogenic inhibitor with the ability to decrease tube formation of vascular endothelial cells and to reduce expression of angiogenic factors of tumor cells.

Reference

Kim MS, Lee YM, Moon EJ, et al. (2000). Anti-angiogenic activity of torilin, a sesquiterpene compound isolated from Torilis japonica. Int J Cancer, 87(2):269-75.

anti-apoptotic, apoptosis, Apoptotic, Bcl-2, Chapter 7 Isolates and Cancer Research, FasL, induces apoptosis, p53, PARP

Millettia reticulata flavonoids

(-)-epicatechin, naringenin, 5,7,3′,5′-tetrahydroxyflavanone, formononetin, isoliquiritigenin, and genistein

Action: Induces apoptosis

A study by Fang, Hsu, Lin & Yen (2010) was done on the vitro anticancer activity of flavonoid derivatives isolated from the stems of M. reticulata Benth. Six flavonoid derivatives including (-)-epicatechin (1), naringenin (2), 5,7,3′,5′-tetrahydroxyflavanone (3), formononetin (4), isoliquiritigenin (5), and genistein (6) were isolated from the stems of M. reticulata Benth.

The structures of 1-6 were determined by spectroscopic methods. The effects of flavonoid derivatives (1-6) on the viability of human cancer cells (including HepG2, SK-Hep-1, Huh7, PLC5, COLO 205, HT-29, and SW 872 cells) were investigated. The results indicated that genistein (6) had the strongest inhibitory activity with an IC(50) value of 16.23 microM in SK-Hep-1 human hepatocellular carcinoma cells. Treatment of SK-Hep-1 cells with genistein (6) caused loss of mitochondrial membrane potential. Western blot data revealed that genistein (6) stimulated an increase in the protein expression of Fas, FasL, and p53. Additionally, treatment with genistein (6) changed the ratio of expression levels of pro- and anti-apoptotic Bcl-2 family members and subsequently induced the activation of caspase-9 and caspase-3, which was followed by cleavage of poly(ADP-ribose) polymerase (PARP). These results demonstrate that genistein (6) induces apoptosis in SK-Hep-1 cells via both Fas- and mitochondria-mediated pathways.

Reference

Fang SC, Hsu CL, Lin HT, Yen GC. 2010 Anticancer effects of flavonoid derivatives isolated from Millettia reticulata Benth in SK-Hep-1 human hepatocellular carcinoma cells. J Agric Food Chem. 2010 Jan 27;58(2):814-20. doi: 10.1021/jf903216r.

Anti-cancer, apoptosis, BAX, Chapter 7 Isolates and Cancer Research, Endometrial cancer, p53, S

Zingiber officinale extract

Cancer: endometrial

Action: Anticancer, antioxidant properties

Terpenoids from Zingiber officinale (TZO) treatment resulted in a rapid and strong increase in intracellular calcium and a 20-40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with TZO. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-α, attenuated the anti-cancer effects of TZO and apoptosis was also not observed in the p53(neg) SKOV-3 cells. Our studies demonstrate that terpenoids from steam distilled extract of ginger mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer (Liu et al., 2012).

The essential oils of ginger (Zingiber officinale) and turmeric (Curcuma longa) contain a large variety of terpenoids, some of which possess anticancer, anti-ulcer, and antioxidant properties. Despite their importance, only four terpene synthases have been identified from the Zingiberaceae family: (+)-germacrene D synthase and (S)-β-bisabolene synthase from ginger rhizome, and α-humulene synthase and β-eudesmol synthase from shampoo ginger (Zingiber zerumbet) rhizome (Koo et al., 2012).

Reference

Koo HJ, Gang DR. (2012) Suites of terpene synthases explain differential terpenoid production in ginger and turmeric tissues. PLoS One. 2012;7(12):e51481. doi: 10.1371/journal.pone.0051481.

Liu Y, Whelan RJ, Pattnaik BR, et al. (2012) Terpenoids from Zingiber officinale (Ginger) induce apoptosis in endometrial cancer cells through the activation of p53. PLoS One. 2012;7(12):e53178. doi: 10.1371/journal.pone.0053178.

angiogenesis, Anti-angiogenic, Anti-cancer, apoptosis, Apoptotic, BAX, Bcl-2, CD31, CDK4, Chapter 7 Isolates and Cancer Research, PCNA, Pro-apoptotic, promotes apoptosis, Rectal cancer, STAT, STAT3, VEGF, VEGF, VEGFR, VEGFR-2

Spica Prunellae Extract

Cancer: Colorectal

Action: Promotes apoptosis, anti-angiogenic, induces angiogenesis

Constitutive activation of STAT3 is one of the major oncogenic pathways involved in the development of various types of malignancies including colorectal cancer (CRC); and thus becomes a promising therapeutic target. Spica Prunellae has long been used as an important component in many traditional Chinese medicine formulas to clinically treat CRC. Previously, Lin et al., (2013) found that Spica Prunellae inhibits CRC cell growth through mitochondrion-mediated apoptosis. Furthermore, we demonstrated its anti-angiogenic activities in vivo and in vitro.

CRC mouse xenograft model was generated by subcutaneous injection of human colon carcinoma HT-29 cells into nude mice. Animals were given intra-gastric administration with 6 g/kg of the ethanol extract of Spica Prunellae (EESP) daily, 5 days a week for 16 days. Body weight and tumor growth were measured every two days. Tumor growth in vivo was determined by measuring the tumor volume and weight. HT-29 cell viability was examined by MTT assay. Cell apoptosis and proliferation in tumors from CRC xenograft mice was evaluated via immunohistochemical staining (IHS) for TUNEL and PCNA, and the intratumoral microvessel density (MVD) was examined by using IHS for the endothelial cell-specific marker CD31. The activation of STAT3 was evaluated by determining its phosphorylation level using IHS. The mRNA and protein expression of Bcl-2, Bax, Cyclin D1, VEGF-A and VEGFR2 was measured by RT-PCR and IHS, respectively.

EESP treatment reduced tumor volume and tumor weight but had no effect on body weight change in CRC mice; decreasedanti-angiogenic cell viability in a dose-dependent manner, suggesting that EESP displays therapeutic efficacy against colon cancer growth in vivo and in vitro, without apparent toxicity. In addition, EESP significantly inhibited the phosphorylation of STAT3 in tumor tissues, indicating its suppressive action on the activation of STAT3 signaling. Consequently, the inhibitory effect of EESP on STAT3 activation resulted in an increase in the pro-apoptotic Bax/Bcl-2 ratio, decrease in the expression of the pro-proliferative Cyclin D1 and CDK4, as well as down-regulation of pro-angiogenic VEGF-A and VEGFR-2 expression. Finally, these molecular effects led to the induction of apoptosis, the inhibition of cell proliferation and tumor angiogenesis.

Spica Prunellae possesses a broad range of anti-cancer activities due to its ability to affect STAT3 pathway, suggesting that Spica Prunellae could be a novel potent therapeutic agent for the treatment of CRC.

Reference

Lin W, Zheng L, Zhuang Q, Zhao J, et al. (2013) Spica prunellae promotes cancer cell apoptosis, inhibits cell proliferation and tumor angiogenesis in a mouse model of colorectal cancer via suppression of stat3 pathway. BMC Complement Altern Med. 2013 Jun 24;13(1):144.

apoptosis, Chapter 7 Isolates and Cancer Research, Chemotherapy, cytotoxic, G2/M, Ovarian cancer, Ovarian cancer cell lines, S

Oplopanax horridus

Cancer: Ovarian

Action: Chemotherapy sensitising, anti-proliferation, apoptosis inducing

To search for more effective treatment of ovarian cancer, Tai et al., (2010) investigated the in vitro anti-proliferation activities of Oplopanax horridus (Devil’s club/OH) root bark extracts, an important medicinal plant of North America, on cisplatin sensitive and resistant human ovarian cancer cell lines. Their data showed that water, 70% ethanol, 100% ethanol, and ethyl acetate extracts of OH inhibited the proliferation of human ovarian cancer cell lines A2780, A2780CP70, OVCAR3, and OVCAR10 in vitro. The respective 50% inhibition (IC(50)) was estimated at 1/256, 1/74, 1/69, 1/53; 1/4156, 1/1847, 1/1029, 1/4530; 1/25,753, 1/3310, 1/3462, 1/5049; and 1/29,916, 1/2912 1/3828, and 1/4232 dilutions. Some combinations of non-cytotoxic dilutions (<IC(50)) of 70% ethanol OH extract with cisplatin and paclitaxel enhanced its anti-proliferation IC(50) on A2780 and A2780CP70 cells. Cell cycle analysis demonstrated that the effect of OH extract on cell cycle was dependent on the concentration tested, blocking cells in the S and G2/M phases. At low concentrations it induced cell death by apoptosis, while at high concentrations, it kills cells by necrosis. Their data showed that OH extracts exhibited significant anti-proliferation effect against both cisplatin sensitive and resistant human ovarian cell lines. Further research might result in discovery of agent(s) that can potentially be useful as an adjunct therapy for ovarian cancer cells. It is one of the few North American medicinal herbs that have been tested for anti-ovarian cancer activities.

Reference

Tai J, Cheung S, Chan E, Hasman D. (2010) Inhibition of human ovarian cancer cell lines by devil’s club Oplopanax horridus. J Ethnopharmacol. 2010 Feb 3;127(2):478-85. doi: 10.1016/j.jep.2009.10.010.

apoptosis, CDK, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, cytotoxic, G1, Glioblastoma, Menopausal Symptoms, p16, p53

Methanol Extract of Angelica sinensis

Cancer: Glioblastoma

Action: Cell-cycle arrest

Glioblastoma multiforme (GBM), the most common malignant tumor of the central nervous system, is a highly vascularized and invasive neoplasm. The annual incidence of GBM was approximately 5–7 per 100,000 people per year in the USA between 1995 and 2008. Because of its malignant properties, rapid growth, diffuse invasion, and resistance to current therapies, the median survival of GBM patients is approximately 50 weeks. Current treatments combine surgery, radiation, and chemoradiotherapy, providing an increase in the median overall survival from 12 to 15 months.

The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis.

AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival.

In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.

The different extracts of A. sinensis, such as water, chloroform, and acetone extracts, have demonstrated antitumor biofunctions (Cheng et al., 2004; Tsai et al., 2005). In this study, AS-M has demonstrated to be a potential antitumor extract isolated from A. sinensis that efficiently inhibits GBM tumor growth. In an in vitro cytotoxic assay, brain tumor cells were sensitive to AS-M and normal fibroblast cells were unsusceptible to AS-M. AS-M dramatically inhibited 90% of the subcutaneous tumor growth and prolonged survival in vivo. AS-M efficiently suppressed tumor growth by inducing cell cycle arrest at the G0-G1 phase and promoting apoptosis. The AS-M mechanism was found to involve the cyclin/CDK/CKI cell cycle regulatory system and the upregulation of p16 and p53 expression.

Source:

Lin Y-L, Lai W-L, Harn H-j, et al (2013) The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors. Evidence-Based Complementary and Alternative Medicine. Volume 2013 (2013), http://dx.doi.org/10.1155/2013/394636

Reference

Cheng, Y.L., et al., (2004) Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosis. Life Sciences, vol. 75, no. 13, pp. 1579–1594, 2004

Tsai, N.M., et al., (2005) The antitumor effects of Angelica sinensis on malignant brain tumors in vitro and in vivo. Clinical Cancer Research, vol. 11, no. 9, pp. 3475–3484, 2005.

Chapter 7 Isolates and Cancer Research, MDR

Polyphenols

Cancer: T-lymphoblastic leukemia

Action: MDR

Natural polyphenols play an important role in tumor inhibition. Righeschi et al., (2012) used a doxorubicin-sensitive acute T-lymphoblastic leukemia cell line (CCRF-CEM) and its multidrug-resistant subline (CEM/ADR5000) to evaluate the activity of 15 plant polyphenols isolated in our laboratory (hypericin and pseudohypericin, verbascoside, ellagic acid, casticin, kaempferol-3-O-(2”,6”-di-E-p-coumaroyl)-glucopyranoside, kaempferol-3-O-(3,4-diacetyl-2,6-di-E-p-coumaroyl) -glucopyranoside, tiliroside, salvianolic acid B, oleuropein, rosmarinic acid, bergenin) or of others from commercial sources (curcumin, epigallocatechin-3-gallate, silymarin). Casticin was the most potent compound (IC50 values of 0.28 ± 0.02 μM in CCRF-CEM and 0.44 ± 0.17 μM in CEM/ADR5000 cells. The IC50 values of the other compounds tested ranged from 1.52 μM to 164.1 μM. A microarray-based mRNA expression profiling of CCRF-CEM cells treated with casticin was performed in order to identify genes with altered expression following casticin treatment. Networks related to NF-κB, p38MAPK, histones H3 and H4, and follicle stimulating hormone were identified.

Reference

Righeschi C, Eichhorn T, Karioti A, Bilia AR, Efferth T. (2012) Microarray-based mRNA expression profiling of leukemia cells treated with the flavonoid, casticin. Cancer Genomics Proteomics. 2012 May-Jun;9(3):143-51.

apoptosis, Apoptotic, BAX, Bcl-2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, Rectal cancer, S

Longan Seed Extract

Cancer: Colorectal

Action: Cell-cycle arrest

Polyphenols of longan seeds (LSP) were extracted and measured by colorimetry. Four CRC cell lines (Colo 320DM, SW480, HT-29 and LoVo) were treated with LSP and assessed for viability by trypan blue exclusion, for cell cycle distribution by flow cytometry, for apoptosis by annexin V labelling and for changes in the levels of proteins involved in cell cycle control or apoptosis by immunoblotting. Total phenol content of LSP was 695 mg g(-1) and total flavonoids were 150 mg g(-1). LSP inhibited the proliferation (25 microg mL(-1)-200 microg mL(-1)) of Colo 320DM, SW480 and HT-29, but not LoVo.

LSP inhibited the proliferation by blocking cell cycle progression during the DNA synthesis phase and inducing apoptotic death. Western blotting indicated that LSP blocks the S phase, reducing the expression of cyclin A and cyclin D1. Colo 320DM and SW480 treated with LSP also showed the activation of caspase 3 and increased Bax : Bcl-2 ratio. LSP induces S phase arrest of the cell cycle and apoptotic death in three CRC cell lines. The results indicate that LSP is a potential novel chemoprevention and treatment agent for colorectal cancer (Chung et al., 2010).

Reference

Chung YC, Lin CC, Chou CC, Hsu CP. (2010) Eur J Clin Invest. 2010 Aug;40(8):713-21. doi: 10.1111/j.1365-2362.2010.02322.x.