Abstract
Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One of the main underlying mechanisms of this resistance is the over-expression of P-glycoprotein (P-gp), an ATP-dependent transmembrane transporter protein encoded by the MDR1 gene. P-gp might transport anti-cancer drugs out of cancer cells and decrease effective intracellular drug concentrations. An effective approach to overcome MDR is to inhibit the function of P-gp or its expression on the surface of cancer cells. Thus, application of MDR reversal agents can be seen as a potentially important means by which to overcome the clinical drug resistance of tumour cells and improve the efficacy of chemotherapy. Recently, research efforts worldwide have focused on reversal mechanisms for MDR and on the identification of reversal agents. Chinese scholars have performed a great deal of exploratory work by screening for efficacy and low toxicity in drug resistance reversal compounds. These compounds may provide more lead compounds with greater activity, leading to the development of more effective therapies for MDR cancer cells. In this review, the function and efficiency of novel compounds derived from traditional Chinese medicines are described.
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References
Gottesman MM, Ling V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 2006;580:998–1009.
Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455:152–62.
Solazzo M, Fantappiè O, Lasagna N, Sassoli C, Nosi D, Mazzanti R. P-gp localization in mitochondria and its functional characterization in multiple drug-resistant cell lines. Exp Cell Res. 2006;312:4070–8.
Hennessy M, Spiers JP. A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res. 2007;55:1–15.
Bergman AM, Pinedo HM, Talianidis I, Veerman G, Loves WJ, van der Wilt CL, et al. Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines. Br J Cancer. 2003;88:1963–70.
Balimane PV, Marino A, Chong S. P-gp inhibition potential in cell-based models: which “calculation” method is the most accurate? AAPS J. 2008;10:577–86.
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.
Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science. 2009;323:1718–22.
Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 2005;5:30.
Sekiya N, Hikiami H, Yokoyama K, Kouta K, Sakakibara I, Shimada Y, et al. Inhibitory effects of Stephania tetrandra S. Moore on free radical-induced lysis of rat red blood cells. Biol Pharm Bull. 2005;28:667–70.
He L, Liu GQ. Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells. Acta Pharmacol Sin. 2002;23:591–6.
Sun AX, Ye ZG, Li CY, Xue BY, Li LF, Cao XF, et al. Synergistic anticancer effects of tetrandrine combined with doxorubicin or vincristine in vitro. Zhongguo Yao Li Xue Bao. 1999;20:69–73 (in Chinese).
Lu XJ, Xu WL, Luo WJ, Wang FC, Chen QY. Effect of tetrandrine on the doxorubicin-induced expression of mdr1 gene in K562 cells. Zhonghua Xue Ye Xue Za Zhi. 2008;29:468–71 (in Chinese).
Fu LW, Zhang YM, Liang YJ, Yang XP, Pan QC. The multidrug resistance of tumour cells was reversed by tetrandrine in vitro and in xenografts derived from human breast adenocarcinoma MCF-7/adr cells. Eur J Cancer. 2002;38:418–26.
Fu L, Liang Y, Deng L, Ding Y, Chen L, Ye Y, et al. Characterization of tetrandrin, a potent inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Chemother Pharmacol. 2004;53:349–56.
Wang JH, Ye ZG, Sun AX, Xue BY, Liang AH, Li CY, et al. Reversal of anti-apoptotic action by tetrandrine in human breast carcinoma multidrug-resistant MCF-7 cells. Zhongguo Zhong Yao Za Zhi. 2002;27:46–50 (in Chinese).
Dai CL, Xiong HY, Tang LF, Zhang X, Liang YJ, Zeng MS, et al. Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice. Cancer Chemother Pharmacol. 2007;60:741–50.
Xu WL, Shen HL, Ao ZF, Chen BA, Xia W, Gao F, et al. Combination of tetrandrine as a potential-reversing agent with daunorubicin, etoposide and cytarabine for the treatment of refractory and relapsed acute myelogenous leukemia. Leuk Res. 2006;30:407–13.
Shrimali D, Shanmugam MK, Kumar AP, Zhang J, Tan BK, Ahn KS, et al. Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer. Cancer Lett. 2013;341:139–49.
Liu A, Chen H, Wei W, Ye S, Liao W, Gong J, et al. Antiproliferative and antimetastatic effects of emodin on human pancreatic cancer. Oncol Rep. 2011;26:81–9.
Sun Y. Chemosensitization by emodin, a plant-derived anti-cancer agent: mechanism of action. Cancer Biol Ther. 2008;7:476–8.
Dorsey JF, Kao GD. Aloe(-emodin) for cancer? More than just a comforting salve. Cancer Biol Ther. 2007;6:89–90.
Liu DL, Bu H, Li H, Chen H, Guo HC, Wang ZH, et al. Emodin reverses gemcitabine resistance in pancreatic cancer cells via the mitochondrial apoptosis pathway in vitro. Int J Oncol. 2012;40:1049–57.
Li J, Liu P, Mao H, Wanga A, Zhang X. Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro. Oncol Rep. 2009;21:1605–10.
Huang XZ, Wang J, Huang C, Chen YY, Shi GY, Hu QS, et al. Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1. Cancer Biol Ther. 2008;7:468–75.
Zhang W, Chen H, Liu DL, Li H, Luo J, Zhang JH, et al. Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-κB and its regulated targets. Int J Oncol. 2013;42:1189–96.
Shinkai K, Akedo H, Mukai M, Imamura F, Isoai A, Kobayashi M, et al. Inhibition of in vitro tumor cell invasion by ginsenoside Rg3. Jpn J Cancer Res. 1996;87:357–62.
Mochizuki M, Yoo YC, Matsuzawa K, Sato K, Saiki I, Tono-oka S, et al. Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)- and 20(S)-ginsenoside-Rg3, of red ginseng. Biol Pharm Bull. 1995;18:1197–202.
Kim ND, Kim EM, Kang KW, Cho MK, Choi SY, Kim SG. Ginsenoside Rg3 inhibits phenylephrine-induced vascular contraction through induction of nitric oxide synthase. Br J Pharmacol. 2003;140:661–70.
Wei X, Chen J, Su F, Su X, Hu T, Hu S. Stereospecificity of ginsenoside Rg3 in promotion of the immune response to ovalbumin in mice. Int Immunol. 2012;24:465–71.
Kim SW, Kwon HY, Chi DW, Shim JH, Park JD, Lee YH, et al. Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg3. Biochem Pharmacol. 2003;65:75–82.
Kwon HY, Kim EH, Kim SW, Kim SN, Park JD, Rhee DK. Selective toxicity of ginsenoside Rg3 on multidrug resistant cells by membrane fluidity modulation. Arch Pharm Res. 2008;31:171–7.
Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin J Integr Med. 2008;14:33–6.
Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55.
Hsu E. Reflections on the ‘discovery’ of the antimalarial qinghao. Br J Clin Pharmacol. 2006;61:666–70.
Yu HP, Cui L, Pan YJ. Reversal of drug resistance in multidrug-resistant MCF-7/ADR cells of breast cancer by artemisinin. Hua Zhong Ke Ji Da Xue Xue Bao Yi Xue Ban. 2011;40:91–4 (in Chinese).
Reungpatthanaphong P, Mankhetkorn S. Modulation of multidrug resistance by artemisinin, artesunate and dihydroartemisinin in K562/adr and GLC4/adr resistant cell lines. Biol Pharm Bull. 2002;25:1555–61.
Liu L, Zuo LF, Guo JW. Reversal of multidrug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett. 2013;6:1475–81.
Huang RL, Chen CC, Huang YL, Hsieh DJ, Hu CP, Chen CF, et al. Osthole increases glycosylation of hepatitis B surface antigen and suppresses the secretion of hepatitis B virus in vitro. Hepatology. 1996;24:508–15.
Liu JH, Zschocke S, Reininger E, Bauer R. Inhibitory effects of Angelica pubescens f. biserrata on 5-lipoxygenase and cyclooxygenase. Planta Med. 1998;64:525–9.
Matsuda H, Tomohiro N, Ido Y, Kubo M. Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol. Biol Pharm Bull. 2002;25:809–12.
Zhang QL, Zhao JH, Bi JJ, Cao JR, Song J, Wu ZZ. Three coumarins from seed of Cnidium monnieri and their multidrug resistance reversal effects. Zhong Chao Yao. 2003;34:104–6 (in Chinese).
Wang XH, Zhang SJ, Guo X, Sun ML, Li QP, Liu HY. Reversal effect and mechanism of osthole on the multidrug-resistance of human bladder cancer cells T24/ADM. Zhongguo Dang Dai Yi Yao. 2012;19:7–9 (in Chinese).
Liou KT, Shen YC, Chen CF, Tsao CM, Tsai SK. The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production. Eur J Pharmacol. 2003;475:19–27.
Teng CM, Chen CC, Ko FN, Lee LG, Huang TF, Chen YP, et al. Two antiplatelet agents from Magnolia officinalis. Thromb Res. 1988;50:757–65.
Liou KT, Lin SM, Huang SS, Chih CL, Tsai SK. Honokiol ameliorates cerebral infarction from ischemia-reperfusion injury in rats. Planta Med. 2003;69:130–4.
Woodbury A, Yu SP, Wei L, García P. Neuro-modulating effects of honokiol: a review. Front Neurol. 2013;4:130.
Tian W, Deng Y, Li L, He H, Sun J, Xu D. Honokiol synergizes chemotherapy drugs in multidrug resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death. Int J Oncol. 2013;42:721–32.
Xu D, Lu Q, Hu X. Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol. Cancer Lett. 2006;243:274–80.
Xue F, Cheng ZY, Liang WT, Chen H, Wang SY, Yao L. Resistance reverse effects of honokiol on multidrug resistance of U937/ADR cell line. Shanhai Jiao Tong Da Xue Xue Bao Yi Xue Ban. 2009;29:1035–9 (in Chinese).
Ishitsuka K, Hideshima T, Hamasaki M, Raje N, Kumar S, Hideshima H, et al. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and-independent apoptosis. Blood. 2005;106:1794–800.
Bailey HH, Mukhtar H. Green tea polyphenols and cancer chemoprevention of genitourinary cancer. Am Soc Clin Oncol Educ Book. 2013;2013:92–6.
Cai YJ, Ma LP, Hou LF, Zhou B, Yang L, Liu ZL. Antioxidant effects of green tea polyphenols on free radical initiated peroxidation of rat liver microsomes. Chem Phys Lipids. 2002;120:109–17.
Chen D, Wan SB, Yang H, Yuan J, Chan TH, Dou QP. EGCG, green tea polyphenols and their synthetic analogs and prodrugs for human cancer prevention and treatment. Adv Clin Chem. 2011;53:155–77.
Xuan W, Wang S, Han C, Chen J. Study on the inhibition of tea pigments on the adhesion between monocyte and endothelial cells. Wei Sheng Yan Jiu. 2001;30:44–6 (in Chinese).
Zhu A, Wang X, Guo Z. Study of tea polyphenol as a reversal agent for carcinoma cell lines’ multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol. 2001;28:735–40.
Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta. 2002;1542:149–59.
Mei Y, Wei D, Liu J. Reversal of cancer multidrug resistance by tea polyphenol in KB cells. J Chemother. 2003;15:260–5.
Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol. 2004;56:1307–14.
Mei Y, Wei D, Liu J. Reversal of multidrug resistance in KB cells with tea polyphenol antioxidant capacity. Cancer Biol Ther. 2005;4:468–73.
Zhang Q, Wei D, Liu J. In vivo reversal of doxorubicin resistance by (-)-epigallocatechin gallate in a solid human carcinoma xenograft. Cancer Lett. 2004;208:179–86.
Jing WG, Zhang J, Zhang LY, Wang DZ, Wang YS, Liu A. Application of a rapid and efficient quantitative analysis method for traditional Chinese medicines: the case study of quality assessment of Salvia miltiorrhiza Bunge. Molecules. 2013;18:6919–35.
Liu CJ, Liu JG, Yu TC. Tanshinone microemulsion reverses multidrug resistance of tumor. Zhongguo Lin Chuang Kang Fu. 2006;10:181–4 (in Chinese).
Jiang YR, Chen KJ. Pharmacological roles of ligustrazine in cardio-/cerebrovascular systems and its progress in researches of clinical application. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013;33:707–11 (in Chinese).
Xie X, Yang Y, Gao QB. Effect of TMP on multidrug resistance reversal and P-gp expression in human breast cancer cell line MCF-7/ADM. Da Lian Da Xue Xue Bao. 2006;27:76–8 (in Chinese).
Sliva D. Cellular and physiological effects of Ganoderma lucidum (Reishi). Mini Rev Med Chem. 2004;4:873–9.
Sadava D, Still DW, Mudry RR, Kane SE. Effect of Ganoderma on drug-sensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Lett. 2009;277:182–9.
Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92.
Brooks TA, Minderman H, O’Loughlin KL, Pera P, Ojima I, Baer MR, et al. Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Mol Cancer Ther. 2003;2:1195–205.
Xie L, Zhai X, Ren L, Meng H, Liu C, Zhu W, et al. Design, synthesis and antitumor activity of novel artemisinin derivatives using hybrid approach. Chem Pharm Bull (Tokyo). 2011;59:984–90.
Morrissey C, Gallis B, Solazzi JW, Kim BJ, Gulati R, Vakar-Lopez F, et al. Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. Anticancer Drugs. 2010;21:423–32.
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This study was supported by Grant No. 20110728 and No. 20130206050YY from Science and Technology Department of Jilin province and National Natural Science Foundation of China (Grant No. 81170632).
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Li, C., Sun, BQ. & Gai, XD. Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours. Clin Transl Oncol 16, 593–598 (2014). https://doi.org/10.1007/s12094-014-1169-7
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DOI: https://doi.org/10.1007/s12094-014-1169-7