Category Archives: ABCG2

A549, ABCG2, Akt, angiogenesis, Anti-cancer, anti-tumor, apoptosis, Apoptotic, BCRP, Bladder cancer, Breast cancer, Chapter 7 Isolates and Cancer Research, EJ, HIF, Lung cancer, MCF-7, MDR, MTOR, PC3, Prostate cancer, VEGF, VEGF

Dauricine

April 19, 2014 brian

Cancer: Prostate, urinary system, breast, lung

Action: MDR

Lung Cancer

Menispermum dauricum DC (Moonseed) contains several alkaloids, of which dauricine can account for as much as 50% of the alkaloids present. In human lung adenocarcinoma A549 cells, these alkaloids activate caspase-3 by activating caspases-8 and -9. Accordingly, these alkaloids induce apoptosis through the apoptosis death receptor and mitochondrial pathways (Wang et al., 2011).

Prostate Cancer

The anti-tumor effects of asiatic moonseed rhizome extraction-dauricine were explored on bladder cancer EJ cell strain, prostate cancer PC-3Mcell strain and primary cell culture system. The main effective component, phenolic alkaloids of Menispermum dauricum, was extracted and separated from asiatic moonseed rhizome by chemical method.

Dauricine had an obvious proliferation inhibition effect on the main tumor cells in urinary system. The minimum drug sensitivity concentration was between 3.81-5.15 µg/mL, and the inhibition ratio increased with the increased concentration. Dauricine, the main effective component extracted from asiatic moonseed rhizome, had good inhibition effect on tumor cells in the urinary system. At the same time, Dauricine has certain inhibition effects on the primary cultured tumor cell (Wang et al., 2012).

Breast Cancer

Serum-starved MCF-7 cells were pretreated for 1 h with different concentrations of dauricine (Dau), followed by incubation with IGF-I for 6 h. Dau significantly inhibited IGF-I-induced HIF-1alpha protein expression but had no effect on HIF-1alpha mRNA expression. However, Dau remarkably suppressed VEGF expression at both protein and mRNA levels in response to IGF-I. Mechanistically, Dau suppressed IGF-I-induced HIF-1alpha and VEGF protein expression mainly by blocking the activation of PI-3K/AKT/mTOR signaling pathway.

Dau inhibits human breast cancer angiogenesis by suppressing HIF-1alpha protein accumulation and VEGF expression, which may provide a novel potential mechanism for the anti-cancer activities of Dau in human breast cancer (Tang et al., 2009).

Breast Cancer; MDR

The potentiation of vincristine-induced apoptosis by tetrandrine, neferine and dauricine isolated from Chinese medicinal plants in the human mammary MCF-7 Multi-drug-resistant cells was investigated. The apoptotic cells induced by vincristine alone accounted for about 10% of all the cancer cells, while the percentage of apoptotic cells induced by a combination of vincristine with tetrandrine, neferine, or dauricine was found to be significantly higher than that by vincristine alone, and their reversal effects were positively correlated with the drug concentration and the exposure time.

In addition, tetrandrine was shown to be the most potent in the reversal efficacy among the three compounds to be tested for apoptosis in vitro. Tetrandrine, neferine and dauricine showed obvious potentiation of vincristine-induced apoptosis in the human mammary MCF-7 multi-drug-resistant cells (Ye et al., 2001).

MDR

Bisbenzylisoquinoline alkaloids are a large family of natural phytochemicals with great potential for clinical use. The interaction between breast cancer resistant protein (BCRP), sometimes called ATP binding cassette protein G2 (ABCG2), and 5 bisbenzylisoquinoline alkaloids (neferine, isoliensinine, liensinine, dauricine and tetrandrine) was evaluated using LLC-PK1/BCRP cell model.

The intracellular accumulation and bi-directional transport studies were conducted, and then molecular docking analysis was carried out employing a homology model of BCRP. This data indicates that BCRP could mediate the excretion of liensinine and dauricine, and thus influence their pharmacological activity and disposition (Tian et al., 2013).

References

Tang XD, Zhou X, Zhou KY. (2009). Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1alpha protein accumulation and vascular endothelial growth factor expression in human breast cancer cells. Acta Pharmacol Sin, 30(5):605-16. doi: 10.1038/aps.2009.8.

Tian Y, Qian S, Jiang Y, et al. (2013). The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids. Int J Pharm, 453(2):371-9. doi: 10.1016/j.ijpharm.2013.05.053.

Wang J, Li Y, Zu XB, Chen MF, Qi L. (2012). Dauricine can inhibit the activity of proliferation of urinary tract tumor cells. Asian Pac J Trop Med, 5(12):973-6. doi: 10.1016/S1995-7645(12)60185-0.

Wang YG, Sun S, Yang WS, Sun FD, Liu Q. (2011). Extract of Menispermum Dauricum induces apoptosis of human lung cancer cell line A549. J Pract Oncol (Chin), 26:343-346.

Ye ZG, Wang JH, Sun AX, et al. (2001). Potentiation of vincristine-induced apoptosis by tetrandrine, neferine and dauricine in the human mammary MCF-7 Multi-drug-resistant cells. Yao Xue Xue Bao, 36(2):96-9.

ABCG2, AIF, anti-apoptotic, Anti-cancer, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Artemisia annua, Bcl-2, BCRP, Breast cancer, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Derivative of artemisinin, Down-regulates, epidermal growth factor receptor, Esophageal cancer, G0/G1, G1, G2/M, ICAM-1, induces apoptosis, Lymphoma, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, Osteosarcoma, Ovarian cancer, p21, p53, Pancreatic cancer, Prostate cancer, Radio-sensitizer, Sarcoma, Skin cancer

Artesunate

April 11, 2014 brian

Cancer: Colon, esophageal., pancreatic, ovarian, multiple myeloma and diffuse large B-cell lymphoma, osteosarcoma, lung, breast, skin, leukemia/lymphoma

Action: Anti-metastatic, MDR, radio-sensitizer

Pulmonary Adenocarcinomas

Artesunate exerts anti-proliferative effects in pulmonary adenocarcinomas. It mediates these anti-neoplastic effects by virtue of activating Bak (Zhou et al., 2012). At the same time, it down-regulates epidermal growth factor receptor expression. This results in augmented non-caspase dependent apoptosis in the adenocarcinoma cells. Artesunate mediated apoptosis is time as well as dose-dependent. Interestingly, AIF and Bim play significant roles in this Bak-dependent accentuated apoptosis (Ma et al., 2011). Adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) expression is also attenuated while transcription of matrix metallopeptidase 7 (MMP-7) is also down-regulated (Zhao et al., 2011). In addition, arsenuate enhances the radio-sensitization of lung carcinoma cells. It mediates this effect by down-regulating cyclin B1 expression, resulting in augmented G2/M phase arrest (Rasheed et al., 2010).

Breast Cancer

Similarly, artesunate exhibits anti-neoplastic effects in breast carcinomas. Artesunate administration is typically accompanied by attenuated turnover as well as accentuated peri-nuclear localization of autophagosomes in the breast carcinoma cells. Mitochondrial outer membrane permeability is typically augmented. As a result, artesunate augments programmed cellular decline in breast carcinoma cells (Hamacher-Brady et al., 2011).

Skin Cancer

Artesunate also exerts anti-neoplastic effects in skin malignancies. It mediates these effects by up-regulating p21. At the same time it down-regulates cyclin D1 (Jiang et al., 2012).

Colon Cancer

Artemisunate significantly inhibited both the invasiveness and anchorage independence of colon cancer SW620 cells in a dose-dependent manner. The protein level of intercellular adhesion molecule 1 (ICAM-1) was down-regulated as relative to the control group.

Artemisunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao & Li, 2008).

Multi-drug resistance; Colon Cancer

A profound cytotoxic action of the antimalarial., artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC50 values) for ART correlated significantly to the cell doubling times (P = 0.00132) and the portion of cells in the G0/G1 (P = 0.02244) or S cell-cycle phases (P = 0.03567).

Efferth et al., (2003) selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data-base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (=12%) genes correlated significantly to the IC50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P = 0.00017).

Multi-drug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent and- independent pathways in isogenic p53+/+ p21WAF1/CIP1+/+, p53-/- p21WAF1/CIP1+/+, and p53+/+ p21WAF1/CIP1-/- colon carcinoma cells.

Multi-drug resistance; Esophageal Cancer

The present study aimed to investigate the correlation between ABCG2 expression and the MDR of esophageal cancer and to estimate the therapeutic benefit of down-regulating ABCG2 expression and reversing chemoresistance in esophageal cells using artesunate (ART).

ART is a noteworthy antimalarial agent, particularly in severe and drug-resistant cancer cases, as ART is able to reverse drug resistance. ART exerted profound anti-cancer activity. The mechanism for the reversal of multi-drug resistance by ART in esophageal carcinoma was analyzed using cellular experiments, but still remains largely unknown (Liu, Zuo, & Guo, 2013).

Pancreatic Cancer

The combination of triptolide and artesunate could inhibit pancreatic cancer cell line growth, and induce apoptosis, accompanied by expression of HSP 20 and HSP 27, indicating important roles in the synergic effects. Moreover, tumor growth was decreased with triptolide and artesunate synergy. Results indicated that triptolide and artesunate in combination at low concentrations can exert synergistic anti-tumor effects in pancreatic cancer cells with potential clinical applications (Liu & Cui, 2013).

Ovarian Cancer

Advanced-stage ovarian cancer (OVCA) has a unifocal origin in the pelvis. Molecular pathways associated with extrapelvic OVCA spread are also associated with metastasis from other human cancers and with overall patient survival. Such pathways represent appealing therapeutic targets for patients with metastatic disease.

Pelvic and extrapelvic OVCA implants demonstrated similar patterns of signaling pathway expression and identical p53 mutations.

However, Marchion et al. (2013) identified 3 molecular pathways/cellular processes that were differentially expressed between pelvic and extrapelvic OVCA samples and between primary/early-stage and metastatic/advanced or recurrent ovarian, oral., and prostate cancers. Furthermore, their expression was associated with overall survival from ovarian cancer (P = .006), colon cancer (1 pathway at P = .005), and leukemia (P = .05). Artesunate-induced TGF-WNT pathway inhibition impaired OVCA cell migration.

Multiple Myeloma, B-cell Lymphoma

Findings indicate that artesunate is a potential drug for treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL) at doses of the same order as currently in use for treatment of malaria without serious adverse effects. Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with down-regulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 µm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 µm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment (Holien et al., 2013).

Osteosarcoma, Leukemia/Lymphoma

Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo (Xu et al. 2011). ART alone or combined with chemotherapy drugs could inhibit the proliferation of B/T lymphocytic tumor cell lines as well ALL primary cells in vitro, probably through the mechanism of apoptosis, which suggest that ART is likely to be a potential drug in the treatment of leukemia/lymphoma (Zeng et al., 2009).

References

Efferth, T., Sauerbrey, A., Olbrich, A., et al. (2003) Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol, 64(2):382-94.

Fan, Y., Zhang, Y.L., Yao, G.T., & Li, Y.K. (2008). Inhibition of Artemisunate on the invasion of human colon cancer line SW620. Lishizzhen Medicine and Materia Medica Research, 19(7), 1740-1741.

Hamacher-Brady, A., Stein, H.A., Turschner, S., et al. (2011). Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011;286(8):6587–6601. doi: 10.1074/jbc.M110.210047.

Holien, T., Olsen, O.E., Misund, K., et al. (2013). Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol, 91(4):339-46. doi: 10.1111/ejh.12176.

Jiang, Z., Chai, J., Chuang, H.H., et al. (2012). Artesunate induces G0/G1 cell-cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells. Anti-cancer Drugs, 23(6):606–613. doi: 10.1097/CAD.0b013e328350e8ac.

Liu, L., Zuo, L.F., Guo, J.W. (2013). Reversal of Multi-drug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett, 6(5):1475-1481.

Liu, Y. & Cui, Y.F. (2013). Synergism of cytotoxicity effects of triptolide and artesunate combination treatment in pancreatic cancer cell lines. Asian Pac J Cancer Prev, 14(9):5243-8.

Ma, H., Yaom Q., Zhang, A.M., et al. (2011). The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules, 16(12):10556–10569. doi: 10.3390/molecules161210556.

Marchion, D.C., Xiong, Y., Chon, H.S., et al. (2013). Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. Am J Obstet Gynecol, S0002-9378(13)00827-2. doi: 10.1016/j.ajog.2013.08.004.

Rasheed, S.A., Efferth, T., Asangani, I.A., Allgayer, H. (2010). First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer, 127(6):1475–1485. doi: 10.1002/ijc.25315.

Xu, Q., Li, Z.X., Peng, H.Q., et al. (2011). Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 12(4):247–255. doi: 10.1631/jzus.B1000373.

Zhao, Y., Jiang, W., Li, B., et al. (2011). Artesunate enhances radiosensitivity of human non-small-cell lung cancer A549 cells via increasing no production to induce cell-cycle arrest at G2/M phase. Int Immunopharmacol, 11(12):2039–2046. doi: 10.1016/j.intimp.2011.08.017.

Zeng, Y., Ni, X., Meng, W.T., Wen, Q., Jia, Y.Q. (2009). Inhibitive effect of artesunate on human lymphoblastic leukemia/lymphoma cells. Sichuan Da Xue Xue Bao Yi Xue Ban, 40(6):1038-43.

Zhou, C., Pan, W., Wang, X.P., Chen, T.S. (2012). Artesunate induces apoptosis via a bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227(12):3778–3786. doi: 10.1002/jcp.24086.

ABC, ABCG2, Anti-cancer, anti-tumor, apoptosis, Apoptotic, Bcl-2, BCRP, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, G2/M, Leukemia, MDR, Multi-Drug Resistance, Multi-drug resistance, p53, Pro-apoptotic, radiotherapy

Multi-drug resistance

April 5, 2014 brian

Multi-drug resistance in cancer chemotherapy refers to the ability of cancer cells to survive from treatment of a wide range of drugs (Meszaros et al., 2009).

In addition to the MDR induced by drugs in early exposure, the MDR cancer cells may subsequently develop cross-resistance to several unexposed and structurally unrelated chemotherapeutic agents (Biedler et al., 1970).

How to tackle the MDR cells in chemotherapy is a pressing issue in cancer treatments. Verapamil was the first known Pgp inhibitor to increase the intracellular concentration of anti-cancer agents in MDR cells by binding to Pgp and inhibiting the Pgp-mediated efflux (Twentyman, 1992). It was believed that anti-cancer drug resistance could be reversed by drug efflux inhibition. Researchers developed and tested a range of Pgp inhibitors to improve the pharmacological effects of chemotherapy in cancer patients (Tsuruo et al., 1981; Stewart et al., 2000; Toppmeyer et al., 2002).

Mechanisms of MDR include decreased uptake of drugs, alterations in cellular pathways and increased active efflux of drugs (Gottesman, 2002; La Porta, 2007; Watson, 1991).

Overexpression of ATP-binding cassette (ABC) transporters is one of the most common mechanisms. Overexpression of the three major ABC transporters, i.e. P-glycoprotein (Pgp), multi-drug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP/ABCG2), is frequently observed in cancer cell lines selected with chemotherapeutic drugs (Szakacs et al., 2006) and critical to clinical drug resistance (Leonard, 2003).

Fractions from 17 clinically used anti-tumor traditional Chinese medicinal herbs were tested for their potential to restore the sensitivity of MCF-7/ADR and A549/Taxol cells to a known anti-neoplastic agent. Five herbs, Curcuma wenyujin, Chrysanthemum indicum, Salvia chinensis, Ligusticum chuanxiong Hort. and Cassia tora L., could sensitize these resistant cancer cells at a non-toxic concentration (10 µg mL–1), and markedly increased doxorubicin accumulation in MCF-7/ADR cells, which necessitates further investigations into the active ingredients of these herbs and their underlying mechanisms (Yang et al., 2011).

Natural sources are a fertile ground to find novel drugs with activity against MDR cancer cells. In some countries, especially China, traditional herbal medicines are often used together with mainstream chemotherapeutic agents. The clinically used traditional Chinese herbs for the treatment of tumor can be classified into four categories based on the theory of Traditional Chinese Medicine (TCM): drugs (CH group) for 'Clearing away Heat and Toxins', drugs (PB group) for 'Promoting Blood Flow to Remove Stasis', drugs for 'Invigoration' and toxic drugs. Drugs for 'Invigoration' have indirect anti-neoplastic action by enhancing an organism's immunity and have been used clinically to minimise radiotherapy- and chemotherapy-induced toxicity (Fu & Chen, 2008; Chai, To, Lin, 2010).

Some of the recent findings on the circumvention of ABC transporters-mediated MDR by various ingredients and extracts of CM and their formulae, based on whether the MDR reversal involved Pgp alteration, are reviewed below.

Saponins

Ginsenosides are the major active components from Panax ginseng (Renshen). Ginsenosides are mainly triterpenoid dammarane derivatives. Several ginsenosides, namely Rg1, Rg3, Re, Rc and Rd inhibited drug efflux (Kim et al., 2003). A combination of purified saponins containing Rb1, Rb2, Rc, Rd, Re and Rg1 reversed MDR whereas individual ginsenosides did not produce any effect (Park et al., 2006). Ginsenosides reversed MDR of several chemotherapeutic drugs such as homoharringtonine, cytarabine, doxorubicin and etoposide in K562/VCR and in a dose-dependent manner in K562/DOX (Gao et al., 2004).

Pgp expression decreased but bcl-2 expression remained the same (Wang, 2003). Rb1 reversed MDR of harringtonolide and vincristine in K562/HHT and HL60/VCR cell lines respectively (Shi et al. , 2005).

Panax notoginseng (Sanqi) total saponins reversed MDR of doxorubicin in MCF-7/DOX and K562/VCR cell lines. The mechanism may be related to the decrease of Pgp expression (Si & Tien, 2005; Liu, Liu, & Fang, 2008).

Rg3, one of the active ginsenosides from Panax ginseng, restored the sensitivity of resistant KBV20 cell line to various anti-cancer drugs, including vincristine, doxorubicin, etoposide and colchicine in a time-and dose-dependent manner. This ginsenoside competitively inhibited the binding of substrate drugs to Pgp and its binding affinity to Pgp was remarkably higher than that of verapamil. In contrast to the dose-dependent effects in vitro, Rg3 increased animal life span in an in vivo MDR model in a dose-independent manner (Kim et al., 2003).

Flavonoids

Quercetin is one of the most widely distributed flavonoids in natural products including Chinese medicinal herbs such as Sophora japonica (Huai). Quercetin inhibited the binding of heat shock factor at the MDR1 promoter, thereby decreasing MDR1 transcription and reducing Pgp expression (Kim et al., 1998). Quercetin also inhibited the overexpression of Pgp mediated by arsenite (Kioka et al., 1992). In HL-60/DOX and K562/DOX cell lines, quercetin enhanced the anti-cancer sensitivity to daunorubicin and decreased Pgp expression (Cai et al., 2004; Cai et al., 2005). MDR reversal effect of quercetin was probably mediated by its action on mitochondrial membrane potential and the induction of apoptosis. Furthermore, quercetin derivatives rather than quercetin itself reversed MDR (Kothan et al., 2004). Quercetin increased the sensitivity of Pgp-overexpressing KBV1 cell line towards vinblastine and paclitaxel in a dose-dependent manner. Among many active flavonoids, quercetin was less potent than kaempferol but more effective than genistein and daidzein in reversing MDR. Genistein and daidzein had no effect on Pgp expression (Limtrakul, Khantamat, & Pintha, 2005).

Although quercetin may be a potential MDR reversing agent, lethal drug-drug interaction between quercetin and digoxin has been reported. Quercetin (40 mg/kg) elevated the peak blood concentration of digoxin and caused sudden death of tested animals (Wang et al., 2004).

Paeonol is a weak calcium channel blocker isolated from the root of Paeonia suffruticosa (Mudan). In K562/DOX cell line, paeonol showed positive MDR reversal effect towards doxorubicin, daunorubicin, vincristine and vinblastine without modulating Pgp expression [100]. In parental K562 cells, paeonol induced apoptosis in a time-and dose-dependent manner (Sun et al., 2004).

Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 (Ganta & Amiji, 2009). Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner (Chang et al., 2006). Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line (Tang et al., 2005). Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line (Ying et al., 2007). The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line (Um et al., 2008). Curcumin derivatives reversed MDR by inhibiting Pgp efflux (Um et al., 2008).

A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal (Um et al., 2008). Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression (Limtrakul, Anuchapreeda, & Buddhasukh, 2004). Tetrahydrocurcumin, the major metabolite of curcumin, inhibited all three major ABC transporters (Limtrakul et al., 2007). Curcumin induced atypical and caspase-independent cell death in MDR cells (Piwocka, Bielak-Mijewska, & Sikora, 2002). In leukaemic cells collected from 78 childhood leukaemia patients, curcumin reduced Pgp expression (Anuchapreeda et al., 2006). A specialized nanoemulsion of curcumin is better than conventional solution form drugs in enhancing the efficiency of drug delivery into the cells, down-regulating Pgp expression, inhibiting the NFκB pathway and promoting apoptotic response (Choi et al., 2008).

Other Compounds

Schizandrins, the active constituents of Schisandra chinensis (Wuweizi), were investigated for their MDR reversal effects. Schizandrin A was the most potent in reversing MDR by enhancing apoptosis and down-regulating Pgp and total protein kinase C expression. The crude extract of Schisandra chinensis reversed the resistance against vincristine in vivo (Huang et al., 2008). Deoxyschizandrin and γ-schizandrin, among the nine dibenzo[a,c]cyclooctadiene lignans examined, enhanced intracellular drug concentration and induced cell-cycle arrest at the G2/M phase when combined with sub-toxic dosages of doxorubicin (Slaninová et al., 2009). Gomisin A, on the other hand, altered Pgp-substrate interaction by binding to Pgp simultaneously with substrates (Wan et al., 2006).

Formulae – injections (See Injectables)

'Shengmai Injection', consisting of Panax ginseng and Ophiopogon japonicus (Maidong), down-regulated Pgp expression in peripheral blood lymphocyte membrane. When used together with oxaliplatin, 5-fluorouracil or folinic acid, the injection prolonged the survival rate of colon cancer patients (Cao et al., 2005). The injection also enhanced the efficacy of tamoxifen and nifedipine in combination therapy (Lin et al., 2002).

'KLT Injection' consisting of the extract of Coix lacryma-jobi (Yiyi) enhanced the anti-cancer activities of paclitaxel and docetaxel and reversed MDR in a dose-dependent manner (Dong, Zheng, & Lu, 2002).

Formulae – powders

'Shenghe Powder', consisting of Panax ginseng, Scorophularia ningpoensis (Xuanshen) and Atractylodes macrocephala (Baizhu), increased the intracellular concentration of vincristine in resistant SGC-7901/VCR cell line, possibly due to the induction of apoptosis and down-regulation of Pgp and bcl-2 expression (Wang et al., 2007).

'Modified Sanwubai Powder', consisting of herbs such as Croton tiglium (Badou), Platycodon grandiflorum (Jiegeng) and Fritillaria thunbergii, induced apoptosis in SGC-7901 cell line and down-regulated the gene expressions of p53, bcl-2, rasP21CD44 and Pgp (Xu et al., 2005).

Formulae – others

Three herbal extracts used to treat diseases other than cancer, namely Ams-11, Fw-13 and Tul-17, greatly enhanced the efficacy of vincristine both in vitro and in vivo and reversed MDR in a dose-dependent manner. Tul-17 inhibited Pgp expression (Qu et al., 2006).

Oil emulsion from Brucea javanica (Yadanzi) reversed MDR when used together with other chemotherapeutic drugs such as vincristine, doxorubicin, cisplatin, mitomycin C, 5-fluorouracil or etoposide, probably due to down-regulation of Pgp expression or inhibition of TOPO II or both (Yu, Wu, Zhang, 2001).

'Sangeng Mixture Decoction', consisting of Reynoutria japonica (Huzhang), Actinidia arguta (Mihouligen) and Geum aleppicum (Shuiyangmeigen), reversed MDR of doxorubicin via down-regulation of Pgp expression (Feng et al., 2003).

FFTLG, a formula containing Actinidia arguta, reversed MDR in K562/DOX cell line by increasing the intracellular doxorubicin concentration (Guo, Xie, Feng, 2002).

R1, consisting of Ligusticum chuanxiong, Curcuma longa and Millettia dielsiana (Jixueteng), enhanced the anti-cancer activities of doxorubicin in MCF-7/DOX via down-regulation of Pgp expression (Chen et al., 2003; Lin, 2007).

Formulae

'Ganli Injection', consisting of matrine and tetramethylpyazine hydrochloride, reversed MDR by increasing the sensitivity of 5-fluorouracil and the intracellular concentration of doxorubicin in BEL-7402/5-FU cell line (Gu et al., 2007).

'Bushen Huayu Jiedu Formula', consisting of Cinnamomum cassia (Rougui), Psoralea corylifolia (Buguzhi) and Rheum palmatum, was tested in A549/DDP cell line and S180 tumor-bearing mice. In vitro, the formula significantly increased the intracellular concentration of cisplatin at high doses and inhibited the activity of calcium channel and LRP-56 expression at both high and low doses. In vivo, the formula improved the serum concentration, reduced the inflow and the release of Ca2+ and inhibited the LRP gene expression (Cao et al., 2004; Cao et al., 2008).

Four CM formulae, namely Glycyrrhiza glabra (GLYC), Hedyotis diffusa (OLEN), a formula consisting of 15 herbs including Cistanche deserticola (Roucongrong), Rabdosia rubescens (Donglingcao) and Zanthoxylum nitidum (Liangmianzhen) (SPES), and a formula consisting of eight herbs including Serenoa repens (Juyezhong), Scutellaria baicalensis (Huangqin), Panax ginseng and Glycyrrhiza glabra (PC-SPES) were cytotoxic to cancer cell lines in a dose-dependent manner. SPES, PC-SPES, OLEN decreased the bcl-2 gene expression and were pro-apoptotic, while GLYC was pro-necrotic without altering the over-expression of bcl-2 in MDR cells. Furthermore, OLEN, SPES and PC-SPES exhibited similar pharmacological effects to etoposide and vincristine (Sadava et al., 2002).

References

Anuchapreeda S, Thanarattanakorn P, Sittipreechacharn S, et al. (2006). Inhibitory effect of curcumin on MDR1 gene expression in patient leukemic cells. Arch Pharm Res, 29(10):866-873

Biedler JL, Riehm H. (1970). Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res, 30:1174-1184.

Cai X, Chen FY, Han JY, et al. (2004). Restorative effect of quercetin on subcellular distribution of daunorubicin in Multi-drug-resistant leukemia cell lines K562/ADM and HL-60/ADM. Chin J Cancer, 23(12):1611-1615.

Cai X, Chen FY, Han JY, et al. (2005). Reversal of Multi-drug resistance of HL-60 adriamycin resistant leukemia cell line by quercetin and its mechanisms. Chin J Oncol, 27(6):326-329.

Cao CM, Ding XD, Wang XH, Liu P. (2005). Clinical study of shengmai injection in its reversing MDR effect in late phase colon carcinoma patients. Shandong J Tradit Chin Med, 24(9):529-532.

Cao Y, Zhang D, Zheng GJ, Yang Y, Zhang J. (2004). Study on drug resistance reversion and mechanism of bushen huayu jiedu formula in lung cancer cells of drug resistance. Shandong J Trad Chin Med, 23(2):100-104.

Cao Y, Xia Q, Meng H, Zhong A. (2008). Pharmacological effects of serum containing chinese medicine bushen huayu jiedu compound recipe in lung cancer drug-resistance cells. Chin J Integr Med, 14(1):46-50.

Chang HY, Pan KL, Ma FC, et al. (2006). The study on reversing mechanism of Multi-drug resistance of K562/DOX cell line by curcumin and erythromycin. Chin J Hem, 27(4):254-258.

Choi BH, Kim CG, Lim Y, Shin SY, Lee YH. (2008). Curcumin down-regulates the Multi-drug resistance mdr1b gene by inhibiting the PI3K/Akt/NF kappa B pathway. Cancer Lett, 259(1):111-118.

Chen XY, Liu JT. (2003). Study on tumor cells' Multi-drug resistance and its reversion by Chinese herbs. J Chin Integr Med, 1(3):221-225.

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ABCG2, AIF, Anti-cancer, apoptosis, ASTC-a-1, A549, CDC25A, Chapter 7 Isolates and Cancer Research, CHK2, Colon Cancer or Colorectal cancer, cytotoxic, Esophageal cancer, G1, Gastric cancer or Stomach cancer, Glioblastoma, ICAM-1, induces apoptosis, LN-229, Lung cancer, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, Ovarian cancer, ROS, SMAD3

Artesunate, oral (See also Injectables)

March 27, 2014 brian

Cancer:
Non-resectable tumors, Retinoblastoma, colon, esophageal., retinoblastoma, ovarian, lung, glioblastoma, MDR, gastric

Action: Anti-cancer

Artesunate is a semisynthetic derivative of the herbal anti-malaria drug artemisinin, which is the active agent from Artemisia annua L. used in traditional Chinese medicine.

Anti-cancer; Canine

The anti-malarial drug artesunate has shown anti-cancer activity in vitro and in preliminary animal experiments, but experience in patients with cancer is very limited. Preclinical studies in dogs indicated morbidity at high dosage levels. The effects of artesunate have been examined in canine cancer cell lines and in canine cancer patients. A safety/efficacy field study with artesunate was conducted in 23 dogs with non-resectable tumors.

Artesunate was administered for 7–385 days at a dosage of 651-1178 (median 922) mg/m(2). No neurological or cardiac toxicity was observed and seven dogs exhibited no adverse effects at all. Fever and haematological/gastrointestinal toxicity, mostly transient, occurred in 16 dogs. Plasma artesunate and DHA levels fell below the limit of detection within 8–12 hours after artesunate administration, while levels after two hours were close to 1 µM. Artesunate produced a long-lasting complete remission in one case of cancer and short-term stabilization of another 7 cases. This study suggests artesunate may be an effective anti-cancer agent in humans (Rutteman, 2013).

Lung Cancer

The exact molecular mechanism by which artesunate induces apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines has been examined, and it was found that artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. Artesunate treatment was found to induce ROS-mediated apoptosis in a concentration- and time-dependent fashion accompanying the loss of mitochondrial potential and subsequent release of Smac and AIF indicative of intrinsic apoptosis pathway. Furthermore, although ART treatment did not induce a significant down-regulation of voltage-dependent anion channel 2 (VDAC2) expression and up-regulation of Bim expression, silencing VDAC2 potently enhanced the artesunate-induced Bak activation and apoptosis which were significantly prevented by silencing Bim.

Collectively, our data firstly demonstrate that artesunate induces Bak-mediated caspase-independent intrinsic apoptosis in which Bim and VDAC2 as well as AIF play important roles in both ASTC-a-1 and A549 cell lines, indicating a potential therapeutic effect of artesunate for lung cancer (Zhou, 2012).

Glioblastoma

Trials that include artesunate in cancer therapy are ongoing due to its action as a powerful inducer of oxidative DNA damage, giving rise to formamidopyrimidine DNA glycosylase-sensitive sites and the formation of 8-oxoguanine and 1,N6-ethenoadenine. Oxidative DNA damage was induced in LN-229 human glioblastoma cells dose-dependently and was paralleled by cell death executed by apoptosis and necrosis, which could be attenuated by radical scavengers such as N-acetyl cysteine.

These data indicate that both homologous recombination and nonhomologous end joining are involved in the repair of artesunate-induced DNA double-strand break (DSB). Artesunate provoked a DNA damage response (DDR) with phosphorylation of ATM, ATR, Chk1, and Chk2.

Overall, these data revealed that artesunate induces oxidative DNA lesions and DSB that continuously increase during the treatment period and accumulate until they trigger discoidin domain receptors (DDR) and finally tumor cell death (Berdelle, 2011).

Esophageal Cancer, MDR

The Eca109/ABCG2 cell line was established by transfecting the ABCG2 gene into Eca109 cells. The Eca109/ABCG2 esophageal cancer cells with ABCG2 gene overexpression were resistant to adriamycin (ADM), daunorubicin (DNR) and mitoxantrone (MIT), which indicated that ABCG2 may be associated with drug resistance in esophageal cancer.

Artesunate (ART) exerted profound anti-cancer activity. The mechanism for the reversal of multi-drug resistance by Art in esophageal carcinoma was analyzed using cellular experiments (Liu, Zuo, & Guo, 2013).

Artesunate was found to stop the growth of esophageal cancer cells transplated subcutaneous tumors in nude mice in the G1 stage. It is hence thought that the role of Artesunate against esophageal carcinoma maybe relate to cell-cycle blockage. Artesunate was also found to increase the expression of SMAD3 and TGF-β1, and reduce the expression of CDC25A and CDC25B which may also play a role in its anti-cancer activity.

Retinoblastoma

Zhao et al. (2013) found that the cytotoxic action of artesunate (ART) is specific for Retinoblastoma (RB) cells in a dose-dependent manner, with low toxicity in normal retina cells. ART is more effective in RB than carboplatin with a markedly strong cytotoxic effect on carboplatin-resistant RB cells. RB had higher CD71 levels at the membrane compared to normal retinal cells. ART is a promising drug exhibiting high selective cytotoxicity even against multi-drug-resistant RB cells.

Gastric Cancer

Artesunate has concentration-dependent inhibitory activities against gastric cancer in vitro and in vivo by promoting cell oncosis through an impact of calcium, vascular endothelial growth factor, and calpain-2 expression (Zhou et al., 2013).

Ovarian Cancer

Colon Cancer

After colon cancer SW620 cells were treated with different doses of Artemisunate, anchorage independence was studied in soft agar colony formation. Invasiveness was assessed by Boyden chamber, and the protein level of intercellular adhesion molecule-1 (ICAM-1) was detected by Western blot assay. Artemisunate significantly inhibited both the invasiveness and anchorage independence in a dose-dependent manner. The protein level of ICAM-1 was down-regulated as relative to the control group.

Artemisunate could potentially inhibit invasion of the colon carcinoma cell line SW620 by down-regulating ICAM-1 expression (Fan, Zhang, Yao, & Li, 2008).

References

Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. (2011). Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM/ATR Damage Response in Cancer Cells. Mol Cancer Ther, 10(12):2224-33. doi: 10.1158/1535-7163.MCT-11-0534.

Fan, Y, Zhang, YL, Yao, GT, & Li, YK. (2008). Inhibition of Artemisunate on the invasion of human colon cancer line SW620. Lishizzhen Medicine and Materia Medica Research, 19(7), 1740-1741.

Liu, L, Zuo, LF, Guo, JW. (2013). Reversal of Multi-drug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett, 6(5): 1475–1481. doi: 10.3892/ol.2013.1545i

Marchion DC, Xiong Y, Chon HS, et al. (2013). Gene expression data reveal common pathways that characterize the unifocal nature of ovarian cancer. Am J Obstet Gynecol, S0002-9378(13)00827-2. doi: 10.1016/j.ajog.2013.08.004.

Rutteman GR, Erich SA, Mol JA, et al. (2013). Safety and Efficacy Field Study of Artesunate for Dogs with Non-resectable Tumors. Anti-cancer Res, 33(5):1819-27.

Zhao F, Wang H, Kunda P, et al. (2013). Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71. Oncol Rep. doi: 10.3892/or.2013.2574.

Zhou C, Pan W, Wang XP, Chen TS. (2012). Artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells. J Cell Physiol, 227(12):3778-86. doi: 10.1002/jcp.24086.

Zhou X, Sun WJ, Wang WM, et al. (2013). Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anti-cancer Drugs, 24(9):920-7. doi: 10.1097/CAD.0b013e328364a109.

5-LOX, ABC, ABCG2, Akt, angiogenesis, anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, attenuation of immune suppression, Bcl-2, Breast cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, chemo-preventive, chemo-preventive activity, Chemoprevention, COC1/DDP, COX-2, Curcuma longa, CXCR-4, DR5, EGFR, Genitourinary cancers, HER-2, IL-1, IL-6, Immune, inflammation, KBV20C, Lung cancer, Lymphoma, MDR, Melanoma, metastasis, Neurological cancers, Neuropathy, Notch, Ovarian cancer, p53, Pancreatic cancer, PI3K, PI3K/Akt, Prostate cancer, Sarcoma, SGC7901/VCR, Squamous cell carcinoma, STAT, TNF, TRAIL, tumor-inhibitory, VEGF, VEGF

Curcumin

March 27, 2014 brian

Cancer: Colorectal., prostate, pancreatic

Action: MDR, chemo-preventive activity, anti-inflammatory, attenuation of immune suppression

Chemo-preventive Activity

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer-preventive drug development. It is derived from the rhizome of Curcuma longa L. and has both anti-oxidant and anti-inflammatory properties; it inhibits chemically-induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. Chemo-preventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis (Kawamori et al., 1999)

Anti-inflammatory

With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor κB (NFκB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-8 (Chan et al., 1998)

Prostate Cancer

In addition, NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin may abrogate their survival mechanisms (Mukhopadhyay et al., 2001).

Pancreatic Cancer

In patients suffering from pancreatic cancer, orally-administered curcumin was found to be well-tolerated and despite limited absorption, had a reasonable impact on biological activity in some patients. This was attributed to its potent nuclear factor-kappaB (NF-kappaB) and tumor-inhibitory properties, against advanced pancreatic cancer (Dhillon et al., 2008)

MDR

Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 (Ganta et al., 2009).

Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner (Chang et al., 2006). Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line (Tang et al., 2005). Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line (Ying et al., 2007).

The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line. Curcumin derivatives reversed MDR by inhibiting Pgp efflux (Um et al., 2008). A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal [72]. Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression (Limtrakul et al., 2004).

Attenuation of Immune Suppression

Curcumin (a chalcone) exhibited toxicity to human neural stem cells (hNSCs). Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines.

The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active.

These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy (Chen et al., 2012).

Cancer Stem Cells

In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size.

Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in 'complete' or 'partial' responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples (Reddy et al., 2011).

Multiple Cancer Effects; Cell-signaling

Curcumin has been shown to interfere with multiple cell signaling pathways, including cell-cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of anti-apoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF- κB, TNF, IL-6, IL-1, COX-2, and 5-LOX).

The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets (Anand et al., 2008).

Anti-inflammatory; Cell-signaling

Curcumin, a liposoluble polyphenolic pigment isolated from the rhizomes of Curcuma longa L. (Zingiberaceae), is another potential candidate for new anti-cancer drug development. Curcumin has been reported to influence many cell-signaling pathways involved in tumor initiation and proliferation. Curcumin inhibits COX-2 activity, cyclin D1 and MMPs overexpresion, NF-kB, STAT and TNF-alpha signaling pathways and regulates the expression of p53 tumor suppressing gene.

Curcumin is well-tolerated but has a reduced systemic bioavailability. Polycurcumins (PCurc 8) and curcumin encapsulated in biodegradable polymeric nanoparticles showed higher bioavailability than curcumin together with a significant tumor growth inhibition in both in vitro and in vivo studies (Cretu et al., 2012). Curcumin also sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5) (Jung et al., 2005).

Curcumin and bioavailability

Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemo-preventive properties in rodents. It possesses poor systemic availability. Marczylo et al. (2007) explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin. Their results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin.

Curcuminoids are poorly water-soluble compounds and to overcome some of the drawbacks of curcuminoids, Aditya et al. (2012) explored the potential of liposomes for the intravenous delivery of curcuminoids. The curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy PC). Curcumin/curcuminoids were encapsulated in phosphatidylcholine vesicles with high yields. Vesicles in the size range around 200 nm were selected for stability and cell experiments. Liposomal curcumin were found to be twofold to sixfold more potent than corresponding curcuminoids. Moreover, the mixture of curcuminoids was found to be more potent than pure curcumin in regard to the anti-oxidant and anti-inflammatory activities (Basnet et al., 2012). Results suggest that the curcumin-phosphatidylcholine complex improves the survival rate by increasing the anti-oxidant activity (Inokuma et al., 2012). Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases (Wang et al., 2012). Data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response (Patzk- et al., 2012).

References

Aditya NP, Chimote G, Gunalan K, et al. (2012). Curcuminoids-loaded liposomes in combination with arteether protects against Plasmodium berghei infection in mice. Exp Parasitol, 131(3):292-9. doi: 10.1016/j.exppara.2012.04.010.

Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. (2008). Curcumin and cancer: An 'old-age' disease with an 'age-old' solution. Cancer Letters, 267(1):133–164. doi: 10.1016/j.canlet.2008.03.025.

Basnet P, Hussain H, Tho I, Skalko-Basnet N. (2012). Liposomal delivery system enhances anti-inflammatory properties of curcumin. J Pharm Sci, 101(2):598-609. doi: 10.1002/jps.22785.

Chan MY, Huang HI, Fenton MR, Fong D. (1998). In Vivo Inhibition of Nitric Oxide Synthase Gene Expression by Curcumin, a Cancer-preventive Natural Product with Anti-Inflammatory Properties. Biochemical Pharmacology, 55(12), 1955-1962.

Chang HY, Pan KL, Ma FC, et al. (2006). The study on reversing mechanism of Multi-drug resistance of K562/DOX cell line by curcumin and erythromycin. Chin J Hem, 27(4):254-258.

Chen SS, Corteling R, Stevanato L, Sinden J. (2012). Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — A Role of Immunomodulation in Chemoprevention. Discovery Medicine.

Cre ţ u E, Trifan A, Vasincu A, Miron A. (2012). Plant-derived anti-cancer agents – curcumin in cancer prevention and treatment. Rev Med Chir Soc Med Nat Iasi, 116(4):1223-9.

Dhillon N, Aggarwal BB, Newman RA, et al. (2008). Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res,14(14):4491-9. doi: 10.1158/1078-0432.CCR-08-0024.

Ganta S, Amiji M. (2009). Coadministration of paclitaxel and curcumin in nanoemulsion formulations To overcome Multi-drug resistance in tumor cells. Mol Pharm, 6(3):928-939. doi: 10.1021/mp800240j.

Inokuma T, Yamanouchi K, Tomonaga T, et al. (2012). Curcumin improves the survival rate after a massive hepatectomy in rats. Hepatogastroenterology, 59(119):2243-7. doi: 10.5754/hge10650.

Jung EM, Lim JH, Lee TJ, et al. (2005). Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5). Carcinogenesis, 26(11):1905-1913.