Clin Transl Oncol DOI 10.1007/s12094-014-1169-7
EDUCATIONAL SERIES
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AD VANCES IN TRANSLATIONAL ONCOLOGY
Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours C. Li • B.-Q. Sun • X.-D. Gai
Received: 3 December 2013 / Accepted: 19 February 2014 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2014
Abstract Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One of the main underlying mechanisms of this resistance is the overexpression 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.
Keywords Multidrug resistance Chinese herbal medicines P-glycoprotein Compound Reversal agent
Introduction Multidrug resistance (MDR) in cancer is a major cause of the failure of chemotherapy in the treatment of cancer patients. MDR in the initial stage of chemotherapy is referred to as intrinsic resistance, while MDR after many cycles of chemotherapy is referred to as acquired resistance. No matter what the type of the resistance, cancer cells become resistant to a single drug or to a family of drugs with identical mechanisms of action, a phenomenon known as classical MDR [1]. They may acquire broad cross-resistance to mechanistically and structurally unrelated drugs. Clinically, the MDR phenotype of cancer cells is due to multiple factors, one of the main underlying mechanisms of MDR is the over-expression of P-glycoprotein (P-gp), an ATP-dependent membrane transporter protein encoded by the MDR1 gene.
P-gp structure and function
C. Li X.-D. Gai (&) Department of Pathology, School of Basic Medical Sciences, Beihua University, 3999 Huashan Road, Jilin 132013, People’s Republic of China e-mail: [email protected] B.-Q. Sun Department of Neural Internal Medicine, Affiliated Hospital of Beihua University, 12 Middle Jiefang Road, Jilin 132013, People’s Republic of China
P-gp is an ATP-driven transmembrane transporter capable of the efflux of a wide variety of structurally diverse and functionally unrelated hydrophobic compounds out of the cell. Its main physiological function is to prevent the absorption of harmful substances and mediate the export of substances to protect the brain, testis and bone marrow in addition to other important tissues and organs and the developing foetus. Juliano first discovered that P-gp was associated with the efflux of drugs [2]. Later, a growing number of studies found MDR could pump out drugs from
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the cytoplasm into the extracellular matrix. MDR is often related to the over-expression of P-gp and has been implicated as a major obstacle to effective chemotherapy for cancer [3]. There are two MDR genes in humans, MDR1 and MDR2. Their gene sequences have high levels of homology. MDR1 is associated with the multidrug resistance of tumours, but the function of MDR2 has not yet been determined [4]. Almost all human tumour cells have different levels of P-gp expression, but some tumour cells exhibiting P-gp over-expression have been found to be insensitive to chemotherapy [5]. Until now, P-gp has been the most widely studied and is the best understood of all the drug transporter proteins [6]. Additionally, P-gp is one of the most important target molecules in the development of MDR reversal agents. P-gp is made up of 1,280 amino acids and has a molecular mass of approximately 170 kDa. The protein has a tandem coupled structure, with 1,220 amino acids constituting two tandem repeat sequences and the other 60 amino acids connecting the two repeat sequences. The basic functional unit of P-gp consists of four domains. Two cytoplasmic nucleotide-binding domains (NBDs) that bind and hydrolyse ATP, plus two highly hydrophobic transmembrane domains (TMDs) that each consists of six transmembrane spanning a-helices that form a substrate membrane-crossing pathway, where the energy from ATP hydrolysis is used to transport substrates across the cell membrane. The X-ray structure of P-gp at 3.8 angstroms shows an internal cavity of approximately 6,000 cubic angstroms with a 30 angstrom separation of the two NBDs. Inside the cavity, there are different drug-binding sites capable of stereo-selectivity based on hydrophobic interactions. Before P-gp combines with ATP, the TMDs form a portal that initially opens to the intracellular space. Upon binding a nucleotide, P-gp undergoes a large conformational change. It becomes closed to the intracellular space and exposed to extracellular space and thus transports the substrate to the extracellular space [7–9]. The discovery of the structure of P-gp provides the molecular basis for drug combination and allows us to elucidate the mechanism of drug catalysis and transport at the molecular level. On this basis, we may reasonably design a drug to adjust and interfere with P-gp function, improve drug sensitivity and prevent the generation of drug resistance.
attention to Chinese herbal medicine with regard to MDR reversal. Recently, pharmacologists worldwide have made great progress in MDR reversal using Chinese herbal medicines and compounds. They have reported many new compounds with the function of MDR reversal. In this article, we will summarise these related compounds and discuss the mechanisms of action of the new MDR reversal agents. Reported MDR reversal compounds from Chinese herbal medicine and their main features are shown in Table 1. Stephania tetrandra Stephania tetrandra (ST) comes from roots of Stephania tetrandra S. MOORE, contains a variety of alkaloids and has been used as an analgesic drug for arthritis for thousands of years in China. ST has been reported to have antiinflammatory and immunosuppressive properties in vitro and in vivo [10]. The main constituent compounds of Stephania tetrandra include tetrandrine (TTD), dauricine (DRC) and daurisoline (DRS). These compounds all belong to the bisbenzylisoquinoline (BBI) alkaloid family of calcium channel blockers. It has been reported that all three compounds can effectively increase the accumulation of drugs and reverse MDR in vitro through modulation of P-gp-mediated drug efflux [11]. TTD is the most widely studied and best understood of all the reversal agents among traditional Chinese medicine compounds. A combination of TTD with doxorubicin or vincristine in vitro demonstrated synergistic anti-cancer effects, and TTD reduced P-gp expression [12, 13]. In mice bearing doxorubicin-resistant human breast cancer (MCF-7/Adr) cells, TTD increased the anti-tumour activities of doxorubicin without significantly increasing toxicity and prolonged the life span of the tumour-bearing mice without any side effects [14–16]. The study showed that TTD reached plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice or CYP 3A4 activity in human liver microsomes [17]. In a recent clinical trial, a combination of tetrandrine, daunorubicin, etoposide and cytarabine had encouraging anti-leukaemic effects in 38 patients with acute myeloid leukaemia [18]. Emodin
Chinese herbal medicines as reversal agents for P-gp-mediated MDR Chinese medicine has long been used in the treatment of tumours, and Chinese herbal medicines have the advantages of low cost, lower toxicity and a greater number of targets. As a result, researchers have paid increasing
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Emodin is an active component of the traditional Chinese medicine Rheum officinale and has extensive pharmacological effects, such as anti-bacterial effects, anti-inflammatory effects and immune suppression [19]. Pharmacological studies have demonstrated that Emodin exhibits anti-cancer effects on several human cancers, including human pancreatic cancer [20–22]. It has been found that Emodin has a
Clin Transl Oncol Table 1 Summary of reported MDR reversal compounds derived from Chinese herbal medicines Compound
Medicinal plant
Reversal of P-gpmediated MDR
Other activity
Stephania tetrandra
Stephania tetrandra S. Moore
?
Calcium channel blockade, analgesic, anti-inflammatory and immunosuppressive effects
Emodin
Rheum officinale
?
Anti-bacterial, anti-inflammatory, immunosuppressive and anti-cancer effects
Ginsenoside Rg3
Red Panax ginseng
?
Inhibiting tumour proliferation, relaxing vessels and modulating immunity
Artemisinin
Artemisia annua
?
Treating fever, anti-malarial effect
Osthole
Cnidium monnieri(L.) Cusson
?
Treating male sexual dysfunction, anti-hepatitis, anti-allergic and anti-inflammatory effects
Honokiol
Magnolia grandiflora
?
Anti-inflammatory, anti-oxidant, anti-thrombotic, anxiolytic and neuroprotective properties
Tea polyphenols
Theaceae
?
Chemical protection, anti-oxidant, anti-atherosclerosis and anti-tumour effects
Tanshinone
Salvia miltiorrhiza
?
To be used in the prevention and treatment of coronary heart disease and cerebrovascular disease
Ligustrazine
Ligusticum chuanxiong Hort
?
Protecting vascular endothelium, preventing platelet aggregation, restraining ischemia–reperfusion injury and resisting oxidative stress
Ganoderma
Ganoderma lucidum
?
Anti-cancer, immune regulatory and anti-oxidant activities
reversing effect on drug-resistant cancer cells [23–26]. Emodin and cisplatin co-treatment remarkably down-regulated MDR1 expression and promoted drug retention in the multidrug resistant prostate carcinoma cell line DU-145. Similar results have been reported in a human pancreatic cancer cell line (Bxpc-3/Gem). Furthermore, the MDR reversal mechanisms of Emodin were also related to the inhibition of hypoxia inducible factor-1 (HIF-1) and survival signalling [25, 26]. Experiments in vivo on tumour-bearing mice showed that Emodin and cisplatin co-treatment inhibited tumour growth partly due to MDR1 down-regulation within tumours [25].
blocks drug efflux. Recently, a study of its effect on membrane fluidity indicated that G-Rg3 decreased the membrane fluidity thereby blocking drug efflux. Additionally, in vivo experiments demonstrated that G-Rg3 prolonged the life span of mice bearing implanted DOXresistant murine leukaemia P388 cells [31, 32]. Clinically, G-Rg3 in combination with chemotherapy can increase the life span of patients with non-small cell lung cancer (NSCLC) after operation [33]. At the present time, G-Rg3 has been approved for use as a clinical antitumour drug in China. Artemisinin
Ginsenoside Rg3 Ginsenoside Rg3 (G-Rg3) is a saponin extracted from Red Panax ginseng. It has been reported to be capable of inhibiting tumour proliferation, relaxing vessels and modulating immunity [27–30]. The accumulation of rhodamine 123 (a P-gp substrate) in MDR carcinoma cells was used to quantitatively examine P-gp functional activity. Some studies have demonstrated that G-Rg3 can increase the accumulation of rhodamine 123 in drugresistant KBV20C cells in a concentration-dependent manner and inhibit [3H]vinblastine efflux and reverse MDR to chemotherapy agents in KBV20C cells. A photoaffinity labelling study with [3H]azidopine revealed that G-Rg3 competed with [3H]azidopine in binding to P-gp. Thus, the reversal mechanism may be that G-Rg3 competes with the anti-cancer drug for binding to P-gp and
Artemisinin (Art) is produced from Artemisia annua, a medicinal herb that has long been used as a tea infusion in traditional Chinese medicine to treat fever and has an anti-malarial effect [34]. The structure of the active substance is a sesquiterpene lactone peroxide [35]. Art and its derivatives have been demonstrated to exert a MDR reversal effect in resistant carcinoma cells [36–38]. It has been reported that Art combined with adriamycin can inhibit the proliferation of MCF-7/ADR cells [36]. The mechanism for the reversal of MDR by Art in MCF7/ADR cells may well be related to the influence of the exchange of drugs between the cytoplasm and cell membrane, inhibiting P-gp expression on the cell membrane, promoting the aggregation of adriamycin in the cytoplasm and enhancing the killing effect of the medicine on tumour cells [36].
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Osthole Osthole is an active constituent found in Cnidium monnieri (L.) Cusson in a high amount and has been used in China for several hundred years as a herbal medicine to treat male sexual dysfunction. It has been reported to have many pharmacological activities, including anti-hepatitis, antiinflammatory, and anti-allergic effects [39–41]. Zhang et al. isolated three active compounds present in the seeds of C. monnieri (L.) Cusson. The three active coumarins obtained were imperatorin (I), edultin (II) and 30 -isobutyryloxy-O-acetyl columbionetin (III). All three compounds exhibited obvious MDR-reversing activities in KBV200 cells, a classical MDR human epidermoid carcinoma cell line [42]. A recent study also showed that Osthole had a reversal effect on the multidrug resistance of the human bladder cancer cells T24/ADM and that the mechanism of reversal was related to down-regulation of the expression of P-gp [43]. Honokiol Honokiol (HNK) is a poly-phenolic compound that is extracted from Magnolia grandiflora, a species of magnolia used in traditional medicines throughout Asia. It is known for its anti-inflammatory, anti-thrombotic, antioxidant, anxiolytic and neuroprotective properties [44–47]. A recent study revealed a novel function of HNK. It has been found that HNK synergised with chemotherapeutic agents in resistant solid and non-solid MCF-7/ADR and HL-60/ADR cell lines, a human breast MDR cancer cell line and a human leukaemia MDR cell line [48]. The mechanism by which HNK reverses MDR has been shown to involve inhibiting the expression of P-gp at the mRNA and protein levels in the MCF-7/ADR cell line. The downregulation of P-gp was accompanied by a partial MDR reversal and increased sensitivity toward chemotherapeutic agents [49]. Furthermore, HNK could enhance sensitivity toward chemotherapeutic agents by induction of caspasedependent and -independent apoptosis, blocking NF-kappa B activation and decreasing the expression of P-gp [50, 51]. Tea polyphenols Tea polyphenols (TP) are compounds extracted from green tea. Green tea belongs to the Theaceae plant family, which originated in China. The main constituents of green tea polyphenols are catechins (flavanols), which comprise four major catechin derivatives: namely, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) [52]. EGCG is abundant and is the most studied catechin. TP are widely believed to
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function as chemical protection, anti-oxidant, anti-cancer and anti-atherosclerosis agents [53–55]. Recently, some studies have showed that TP are not only anti-tumour agents but also modulators of MDR. The MDR reversal mechanism of TP seems to be due to their inhibition of the activity of P-gp [56, 57]. A further study of the mechanism showed that down-regulation of MDR1 gene expression and inhibition of ATPase activity could result in a decreased extrusion of anti-cancer drugs and an increased accumulation of anti-cancer drugs within drug-resistant cells [58, 59]. The reversal effect of TP on MDR was partly related to regulating the doxorubicin-induced intracellular concentration of reactive oxygen species [60]. Moreover, TP could chemosensitise resistant tumour cells to doxorubicin in vivo through an increase in the accumulation of doxorubicin in the tumours [61]. Others Salvia miltiorrhiza is a commonly used huoxue huayu Chinese traditional medicine, and one of its effective components is Tanshinone. S. miltiorrhiza injections are used in the prevention and treatment of coronary heart disease and cerebrovascular disease [62]. Liu et al. investigated the reversal effects of tanshinone microemulsion on ADM-resistant cell lines (K562/ADM). The result showed that tanshinone microemulsion of 0.5 mg/L could increase the intracellular concentration of ADM, which was consistent with a down-regulation of P-gp expression [63]. Roots of Ligusticum chuanxiong Hort are also a commonly used traditional Chinese medicine, and their predominant constituent is Ligustrazine. Ligustrazine is known to exert various effects in vitro and in vivo, such as protecting vascular endothelium, preventing platelet aggregation, restraining ischemia–reperfusion injury and providing resistance to oxidative stress [64]. Xie et al. [65] found that non-cytotoxic and low-cytotoxic doses of Ligustrazine could significantly decrease the IC50 value of ADM to MCF-7/ADM and the reversal mechanism might be related to inhibiting P-gp expression in MCF-7/ADM. Ganoderma lucidum is a widely used herb in traditional Chinese medicine. The Ganoderma species are being investigated with regard to a variety of potential therapeutic benefits, such as anti-cancer effects, immune regulatory effects and anti-oxidant activities [66]. The extracts of several species of Ganoderma are cytotoxic to drug-resistant SCLC cells [67].
Conclusion The relevant data show that, in a sense, the deaths of more than 90 % of cancer patients are more or less related to
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tumour MDR [68]. However, there are as yet no effective tumour MDR reversal agents used in clinical practice. Therefore, the discovery of a lead compound may provide therapeutics that are able to reverse the MDR of tumour cells. Through thousands of years of research and practice, traditional Chinese medicine has provided valuable material resources and a good foundation for finding novel reversal agents. Taxane-based reversal agents hold promise for development as clinical MDR reversal agents and warrant more preclinical analysis to determine their pharmacokinetic interactions and efficacy [69]. The novel artemisinin derivatives displayed more potent anti-cancer activity than the corresponding lead compound, artemisinin [70, 71]. Therefore, the continued development of novel compounds from traditional Chinese medicine may provide more lead compounds with greater activity, leading to the development of more effective therapies for MDR cancer cells. Acknowledgments 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). Conflict of interest
None.
References 1. 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. 2. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455:152–62. 3. Solazzo M, Fantappie` O, Lasagna N, Sassoli C, Nosi D, Mazzanti R. P-gp localization in mitochondria and its functional characterization in multiple drugresistant cell lines. Exp Cell Res. 2006;312:4070–8. 4. Hennessy M, Spiers JP. A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res. 2007;55:1–15. 5. 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. 6. 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. 7. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATPdependent transporters. Nat Rev Cancer. 2002;2:48–58. 8. 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. 9. Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 2005;5:30. 10. 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. 11. 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. 12. 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). 13. 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). 14. 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.
15. 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. 16. Wang JH, Ye ZG, Sun AX, Xue BY, Liang AH, Li CY, et al. Reversal of antiapoptotic action by tetrandrine in human breast carcinoma multidrug-resistant MCF-7 cells. Zhongguo Zhong Yao Za Zhi. 2002;27:46–50 (in Chinese). 17. 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. 18. 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. 19. 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. 20. 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. 21. Sun Y. Chemosensitization by emodin, a plant-derived anti-cancer agent: mechanism of action. Cancer Biol Ther. 2008;7:476–8. 22. Dorsey JF, Kao GD. Aloe(-emodin) for cancer? More than just a comforting salve. Cancer Biol Ther. 2007;6:89–90. 23. 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. 24. 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. 25. 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. 26. 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-jB and its regulated targets. Int J Oncol. 2013;42:1189–96. 27. 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. 28. 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. 29. 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. 30. 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. 31. 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. 32. 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. 33. 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. 34. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55. 35. Hsu E. Reflections on the ‘discovery’ of the antimalarial qinghao. Br J Clin Pharmacol. 2006;61:666–70. 36. Yu HP, Cui L, Pan YJ. Reversal of drug resistance in multidrug-resistant MCF7/ADR cells of breast cancer by artemisinin. Hua Zhong Ke Ji Da Xue Xue Bao Yi Xue Ban. 2011;40:91–4 (in Chinese). 37. 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. 38. 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. 39. 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. 40. 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. 41. 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.
123
Clin Transl Oncol 42. 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). 43. 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). 44. 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. 45. 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. 46. 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. 47. Woodbury A, Yu SP, Wei L, Garcı´a P. Neuro-modulating effects of honokiol: a review. Front Neurol. 2013;4:130. 48. 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. 49. 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. 50. 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). 51. 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. 52. Bailey HH, Mukhtar H. Green tea polyphenols and cancer chemoprevention of genitourinary cancer. Am Soc Clin Oncol Educ Book. 2013;2013:92–6. 53. 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. 54. 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. 55. 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). 56. 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.
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57. 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. 58. Mei Y, Wei D, Liu J. Reversal of cancer multidrug resistance by tea polyphenol in KB cells. J Chemother. 2003;15:260–5. 59. Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol. 2004;56:1307–14. 60. 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. 61. 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. 62. 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. 63. Liu CJ, Liu JG, Yu TC. Tanshinone microemulsion reverses multidrug resistance of tumor. Zhongguo Lin Chuang Kang Fu. 2006;10:181–4 (in Chinese). 64. 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). 65. 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). 66. Sliva D. Cellular and physiological effects of Ganoderma lucidum (Reishi). Mini Rev Med Chem. 2004;4:873–9. 67. Sadava D, Still DW, Mudry RR, Kane SE. Effect of Ganoderma on drugsensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Lett. 2009;277:182–9. 68. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92. 69. 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. 70. 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. 71. 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.
EDUCATIONAL SERIES
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BLUE SERIES
AD VANCES IN TRANSLATIONAL ONCOLOGY
Compounds from Chinese herbal medicines as reversal agents for P-glycoprotein-mediated multidrug resistance in tumours C. Li • B.-Q. Sun • X.-D. Gai
Received: 3 December 2013 / Accepted: 19 February 2014 Ó Federacio´n de Sociedades Espan˜olas de Oncologı´a (FESEO) 2014
Abstract Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy. One of the main underlying mechanisms of this resistance is the overexpression 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.
Keywords Multidrug resistance Chinese herbal medicines P-glycoprotein Compound Reversal agent
Introduction Multidrug resistance (MDR) in cancer is a major cause of the failure of chemotherapy in the treatment of cancer patients. MDR in the initial stage of chemotherapy is referred to as intrinsic resistance, while MDR after many cycles of chemotherapy is referred to as acquired resistance. No matter what the type of the resistance, cancer cells become resistant to a single drug or to a family of drugs with identical mechanisms of action, a phenomenon known as classical MDR [1]. They may acquire broad cross-resistance to mechanistically and structurally unrelated drugs. Clinically, the MDR phenotype of cancer cells is due to multiple factors, one of the main underlying mechanisms of MDR is the over-expression of P-glycoprotein (P-gp), an ATP-dependent membrane transporter protein encoded by the MDR1 gene.
P-gp structure and function
C. Li X.-D. Gai (&) Department of Pathology, School of Basic Medical Sciences, Beihua University, 3999 Huashan Road, Jilin 132013, People’s Republic of China e-mail: [email protected] B.-Q. Sun Department of Neural Internal Medicine, Affiliated Hospital of Beihua University, 12 Middle Jiefang Road, Jilin 132013, People’s Republic of China
P-gp is an ATP-driven transmembrane transporter capable of the efflux of a wide variety of structurally diverse and functionally unrelated hydrophobic compounds out of the cell. Its main physiological function is to prevent the absorption of harmful substances and mediate the export of substances to protect the brain, testis and bone marrow in addition to other important tissues and organs and the developing foetus. Juliano first discovered that P-gp was associated with the efflux of drugs [2]. Later, a growing number of studies found MDR could pump out drugs from
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the cytoplasm into the extracellular matrix. MDR is often related to the over-expression of P-gp and has been implicated as a major obstacle to effective chemotherapy for cancer [3]. There are two MDR genes in humans, MDR1 and MDR2. Their gene sequences have high levels of homology. MDR1 is associated with the multidrug resistance of tumours, but the function of MDR2 has not yet been determined [4]. Almost all human tumour cells have different levels of P-gp expression, but some tumour cells exhibiting P-gp over-expression have been found to be insensitive to chemotherapy [5]. Until now, P-gp has been the most widely studied and is the best understood of all the drug transporter proteins [6]. Additionally, P-gp is one of the most important target molecules in the development of MDR reversal agents. P-gp is made up of 1,280 amino acids and has a molecular mass of approximately 170 kDa. The protein has a tandem coupled structure, with 1,220 amino acids constituting two tandem repeat sequences and the other 60 amino acids connecting the two repeat sequences. The basic functional unit of P-gp consists of four domains. Two cytoplasmic nucleotide-binding domains (NBDs) that bind and hydrolyse ATP, plus two highly hydrophobic transmembrane domains (TMDs) that each consists of six transmembrane spanning a-helices that form a substrate membrane-crossing pathway, where the energy from ATP hydrolysis is used to transport substrates across the cell membrane. The X-ray structure of P-gp at 3.8 angstroms shows an internal cavity of approximately 6,000 cubic angstroms with a 30 angstrom separation of the two NBDs. Inside the cavity, there are different drug-binding sites capable of stereo-selectivity based on hydrophobic interactions. Before P-gp combines with ATP, the TMDs form a portal that initially opens to the intracellular space. Upon binding a nucleotide, P-gp undergoes a large conformational change. It becomes closed to the intracellular space and exposed to extracellular space and thus transports the substrate to the extracellular space [7–9]. The discovery of the structure of P-gp provides the molecular basis for drug combination and allows us to elucidate the mechanism of drug catalysis and transport at the molecular level. On this basis, we may reasonably design a drug to adjust and interfere with P-gp function, improve drug sensitivity and prevent the generation of drug resistance.
attention to Chinese herbal medicine with regard to MDR reversal. Recently, pharmacologists worldwide have made great progress in MDR reversal using Chinese herbal medicines and compounds. They have reported many new compounds with the function of MDR reversal. In this article, we will summarise these related compounds and discuss the mechanisms of action of the new MDR reversal agents. Reported MDR reversal compounds from Chinese herbal medicine and their main features are shown in Table 1. Stephania tetrandra Stephania tetrandra (ST) comes from roots of Stephania tetrandra S. MOORE, contains a variety of alkaloids and has been used as an analgesic drug for arthritis for thousands of years in China. ST has been reported to have antiinflammatory and immunosuppressive properties in vitro and in vivo [10]. The main constituent compounds of Stephania tetrandra include tetrandrine (TTD), dauricine (DRC) and daurisoline (DRS). These compounds all belong to the bisbenzylisoquinoline (BBI) alkaloid family of calcium channel blockers. It has been reported that all three compounds can effectively increase the accumulation of drugs and reverse MDR in vitro through modulation of P-gp-mediated drug efflux [11]. TTD is the most widely studied and best understood of all the reversal agents among traditional Chinese medicine compounds. A combination of TTD with doxorubicin or vincristine in vitro demonstrated synergistic anti-cancer effects, and TTD reduced P-gp expression [12, 13]. In mice bearing doxorubicin-resistant human breast cancer (MCF-7/Adr) cells, TTD increased the anti-tumour activities of doxorubicin without significantly increasing toxicity and prolonged the life span of the tumour-bearing mice without any side effects [14–16]. The study showed that TTD reached plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice or CYP 3A4 activity in human liver microsomes [17]. In a recent clinical trial, a combination of tetrandrine, daunorubicin, etoposide and cytarabine had encouraging anti-leukaemic effects in 38 patients with acute myeloid leukaemia [18]. Emodin
Chinese herbal medicines as reversal agents for P-gp-mediated MDR Chinese medicine has long been used in the treatment of tumours, and Chinese herbal medicines have the advantages of low cost, lower toxicity and a greater number of targets. As a result, researchers have paid increasing
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Emodin is an active component of the traditional Chinese medicine Rheum officinale and has extensive pharmacological effects, such as anti-bacterial effects, anti-inflammatory effects and immune suppression [19]. Pharmacological studies have demonstrated that Emodin exhibits anti-cancer effects on several human cancers, including human pancreatic cancer [20–22]. It has been found that Emodin has a
Clin Transl Oncol Table 1 Summary of reported MDR reversal compounds derived from Chinese herbal medicines Compound
Medicinal plant
Reversal of P-gpmediated MDR
Other activity
Stephania tetrandra
Stephania tetrandra S. Moore
?
Calcium channel blockade, analgesic, anti-inflammatory and immunosuppressive effects
Emodin
Rheum officinale
?
Anti-bacterial, anti-inflammatory, immunosuppressive and anti-cancer effects
Ginsenoside Rg3
Red Panax ginseng
?
Inhibiting tumour proliferation, relaxing vessels and modulating immunity
Artemisinin
Artemisia annua
?
Treating fever, anti-malarial effect
Osthole
Cnidium monnieri(L.) Cusson
?
Treating male sexual dysfunction, anti-hepatitis, anti-allergic and anti-inflammatory effects
Honokiol
Magnolia grandiflora
?
Anti-inflammatory, anti-oxidant, anti-thrombotic, anxiolytic and neuroprotective properties
Tea polyphenols
Theaceae
?
Chemical protection, anti-oxidant, anti-atherosclerosis and anti-tumour effects
Tanshinone
Salvia miltiorrhiza
?
To be used in the prevention and treatment of coronary heart disease and cerebrovascular disease
Ligustrazine
Ligusticum chuanxiong Hort
?
Protecting vascular endothelium, preventing platelet aggregation, restraining ischemia–reperfusion injury and resisting oxidative stress
Ganoderma
Ganoderma lucidum
?
Anti-cancer, immune regulatory and anti-oxidant activities
reversing effect on drug-resistant cancer cells [23–26]. Emodin and cisplatin co-treatment remarkably down-regulated MDR1 expression and promoted drug retention in the multidrug resistant prostate carcinoma cell line DU-145. Similar results have been reported in a human pancreatic cancer cell line (Bxpc-3/Gem). Furthermore, the MDR reversal mechanisms of Emodin were also related to the inhibition of hypoxia inducible factor-1 (HIF-1) and survival signalling [25, 26]. Experiments in vivo on tumour-bearing mice showed that Emodin and cisplatin co-treatment inhibited tumour growth partly due to MDR1 down-regulation within tumours [25].
blocks drug efflux. Recently, a study of its effect on membrane fluidity indicated that G-Rg3 decreased the membrane fluidity thereby blocking drug efflux. Additionally, in vivo experiments demonstrated that G-Rg3 prolonged the life span of mice bearing implanted DOXresistant murine leukaemia P388 cells [31, 32]. Clinically, G-Rg3 in combination with chemotherapy can increase the life span of patients with non-small cell lung cancer (NSCLC) after operation [33]. At the present time, G-Rg3 has been approved for use as a clinical antitumour drug in China. Artemisinin
Ginsenoside Rg3 Ginsenoside Rg3 (G-Rg3) is a saponin extracted from Red Panax ginseng. It has been reported to be capable of inhibiting tumour proliferation, relaxing vessels and modulating immunity [27–30]. The accumulation of rhodamine 123 (a P-gp substrate) in MDR carcinoma cells was used to quantitatively examine P-gp functional activity. Some studies have demonstrated that G-Rg3 can increase the accumulation of rhodamine 123 in drugresistant KBV20C cells in a concentration-dependent manner and inhibit [3H]vinblastine efflux and reverse MDR to chemotherapy agents in KBV20C cells. A photoaffinity labelling study with [3H]azidopine revealed that G-Rg3 competed with [3H]azidopine in binding to P-gp. Thus, the reversal mechanism may be that G-Rg3 competes with the anti-cancer drug for binding to P-gp and
Artemisinin (Art) is produced from Artemisia annua, a medicinal herb that has long been used as a tea infusion in traditional Chinese medicine to treat fever and has an anti-malarial effect [34]. The structure of the active substance is a sesquiterpene lactone peroxide [35]. Art and its derivatives have been demonstrated to exert a MDR reversal effect in resistant carcinoma cells [36–38]. It has been reported that Art combined with adriamycin can inhibit the proliferation of MCF-7/ADR cells [36]. The mechanism for the reversal of MDR by Art in MCF7/ADR cells may well be related to the influence of the exchange of drugs between the cytoplasm and cell membrane, inhibiting P-gp expression on the cell membrane, promoting the aggregation of adriamycin in the cytoplasm and enhancing the killing effect of the medicine on tumour cells [36].
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Osthole Osthole is an active constituent found in Cnidium monnieri (L.) Cusson in a high amount and has been used in China for several hundred years as a herbal medicine to treat male sexual dysfunction. It has been reported to have many pharmacological activities, including anti-hepatitis, antiinflammatory, and anti-allergic effects [39–41]. Zhang et al. isolated three active compounds present in the seeds of C. monnieri (L.) Cusson. The three active coumarins obtained were imperatorin (I), edultin (II) and 30 -isobutyryloxy-O-acetyl columbionetin (III). All three compounds exhibited obvious MDR-reversing activities in KBV200 cells, a classical MDR human epidermoid carcinoma cell line [42]. A recent study also showed that Osthole had a reversal effect on the multidrug resistance of the human bladder cancer cells T24/ADM and that the mechanism of reversal was related to down-regulation of the expression of P-gp [43]. Honokiol Honokiol (HNK) is a poly-phenolic compound that is extracted from Magnolia grandiflora, a species of magnolia used in traditional medicines throughout Asia. It is known for its anti-inflammatory, anti-thrombotic, antioxidant, anxiolytic and neuroprotective properties [44–47]. A recent study revealed a novel function of HNK. It has been found that HNK synergised with chemotherapeutic agents in resistant solid and non-solid MCF-7/ADR and HL-60/ADR cell lines, a human breast MDR cancer cell line and a human leukaemia MDR cell line [48]. The mechanism by which HNK reverses MDR has been shown to involve inhibiting the expression of P-gp at the mRNA and protein levels in the MCF-7/ADR cell line. The downregulation of P-gp was accompanied by a partial MDR reversal and increased sensitivity toward chemotherapeutic agents [49]. Furthermore, HNK could enhance sensitivity toward chemotherapeutic agents by induction of caspasedependent and -independent apoptosis, blocking NF-kappa B activation and decreasing the expression of P-gp [50, 51]. Tea polyphenols Tea polyphenols (TP) are compounds extracted from green tea. Green tea belongs to the Theaceae plant family, which originated in China. The main constituents of green tea polyphenols are catechins (flavanols), which comprise four major catechin derivatives: namely, epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) [52]. EGCG is abundant and is the most studied catechin. TP are widely believed to
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function as chemical protection, anti-oxidant, anti-cancer and anti-atherosclerosis agents [53–55]. Recently, some studies have showed that TP are not only anti-tumour agents but also modulators of MDR. The MDR reversal mechanism of TP seems to be due to their inhibition of the activity of P-gp [56, 57]. A further study of the mechanism showed that down-regulation of MDR1 gene expression and inhibition of ATPase activity could result in a decreased extrusion of anti-cancer drugs and an increased accumulation of anti-cancer drugs within drug-resistant cells [58, 59]. The reversal effect of TP on MDR was partly related to regulating the doxorubicin-induced intracellular concentration of reactive oxygen species [60]. Moreover, TP could chemosensitise resistant tumour cells to doxorubicin in vivo through an increase in the accumulation of doxorubicin in the tumours [61]. Others Salvia miltiorrhiza is a commonly used huoxue huayu Chinese traditional medicine, and one of its effective components is Tanshinone. S. miltiorrhiza injections are used in the prevention and treatment of coronary heart disease and cerebrovascular disease [62]. Liu et al. investigated the reversal effects of tanshinone microemulsion on ADM-resistant cell lines (K562/ADM). The result showed that tanshinone microemulsion of 0.5 mg/L could increase the intracellular concentration of ADM, which was consistent with a down-regulation of P-gp expression [63]. Roots of Ligusticum chuanxiong Hort are also a commonly used traditional Chinese medicine, and their predominant constituent is Ligustrazine. Ligustrazine is known to exert various effects in vitro and in vivo, such as protecting vascular endothelium, preventing platelet aggregation, restraining ischemia–reperfusion injury and providing resistance to oxidative stress [64]. Xie et al. [65] found that non-cytotoxic and low-cytotoxic doses of Ligustrazine could significantly decrease the IC50 value of ADM to MCF-7/ADM and the reversal mechanism might be related to inhibiting P-gp expression in MCF-7/ADM. Ganoderma lucidum is a widely used herb in traditional Chinese medicine. The Ganoderma species are being investigated with regard to a variety of potential therapeutic benefits, such as anti-cancer effects, immune regulatory effects and anti-oxidant activities [66]. The extracts of several species of Ganoderma are cytotoxic to drug-resistant SCLC cells [67].
Conclusion The relevant data show that, in a sense, the deaths of more than 90 % of cancer patients are more or less related to
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tumour MDR [68]. However, there are as yet no effective tumour MDR reversal agents used in clinical practice. Therefore, the discovery of a lead compound may provide therapeutics that are able to reverse the MDR of tumour cells. Through thousands of years of research and practice, traditional Chinese medicine has provided valuable material resources and a good foundation for finding novel reversal agents. Taxane-based reversal agents hold promise for development as clinical MDR reversal agents and warrant more preclinical analysis to determine their pharmacokinetic interactions and efficacy [69]. The novel artemisinin derivatives displayed more potent anti-cancer activity than the corresponding lead compound, artemisinin [70, 71]. Therefore, the continued development of novel compounds from traditional Chinese medicine may provide more lead compounds with greater activity, leading to the development of more effective therapies for MDR cancer cells. Acknowledgments 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). Conflict of interest
None.
References 1. 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. 2. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976;455:152–62. 3. Solazzo M, Fantappie` O, Lasagna N, Sassoli C, Nosi D, Mazzanti R. P-gp localization in mitochondria and its functional characterization in multiple drugresistant cell lines. Exp Cell Res. 2006;312:4070–8. 4. Hennessy M, Spiers JP. A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol Res. 2007;55:1–15. 5. 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. 6. 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. 7. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATPdependent transporters. Nat Rev Cancer. 2002;2:48–58. 8. 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. 9. Choi CH. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 2005;5:30. 10. 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. 11. 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. 12. 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). 13. 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). 14. 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.
15. 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. 16. Wang JH, Ye ZG, Sun AX, Xue BY, Liang AH, Li CY, et al. Reversal of antiapoptotic action by tetrandrine in human breast carcinoma multidrug-resistant MCF-7 cells. Zhongguo Zhong Yao Za Zhi. 2002;27:46–50 (in Chinese). 17. 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. 18. 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. 19. 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. 20. 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. 21. Sun Y. Chemosensitization by emodin, a plant-derived anti-cancer agent: mechanism of action. Cancer Biol Ther. 2008;7:476–8. 22. Dorsey JF, Kao GD. Aloe(-emodin) for cancer? More than just a comforting salve. Cancer Biol Ther. 2007;6:89–90. 23. 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. 24. 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. 25. 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. 26. 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-jB and its regulated targets. Int J Oncol. 2013;42:1189–96. 27. 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. 28. 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. 29. 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. 30. 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. 31. 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. 32. 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. 33. 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. 34. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55. 35. Hsu E. Reflections on the ‘discovery’ of the antimalarial qinghao. Br J Clin Pharmacol. 2006;61:666–70. 36. Yu HP, Cui L, Pan YJ. Reversal of drug resistance in multidrug-resistant MCF7/ADR cells of breast cancer by artemisinin. Hua Zhong Ke Ji Da Xue Xue Bao Yi Xue Ban. 2011;40:91–4 (in Chinese). 37. 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. 38. 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. 39. 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. 40. 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. 41. 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.
123
Clin Transl Oncol 42. 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). 43. 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). 44. 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. 45. 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. 46. 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. 47. Woodbury A, Yu SP, Wei L, Garcı´a P. Neuro-modulating effects of honokiol: a review. Front Neurol. 2013;4:130. 48. 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. 49. 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. 50. 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). 51. 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. 52. Bailey HH, Mukhtar H. Green tea polyphenols and cancer chemoprevention of genitourinary cancer. Am Soc Clin Oncol Educ Book. 2013;2013:92–6. 53. 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. 54. 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. 55. 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). 56. 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.
123
57. 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. 58. Mei Y, Wei D, Liu J. Reversal of cancer multidrug resistance by tea polyphenol in KB cells. J Chemother. 2003;15:260–5. 59. Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol. 2004;56:1307–14. 60. 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. 61. 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. 62. 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. 63. Liu CJ, Liu JG, Yu TC. Tanshinone microemulsion reverses multidrug resistance of tumor. Zhongguo Lin Chuang Kang Fu. 2006;10:181–4 (in Chinese). 64. 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). 65. 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). 66. Sliva D. Cellular and physiological effects of Ganoderma lucidum (Reishi). Mini Rev Med Chem. 2004;4:873–9. 67. Sadava D, Still DW, Mudry RR, Kane SE. Effect of Ganoderma on drugsensitive and multidrug-resistant small-cell lung carcinoma cells. Cancer Lett. 2009;277:182–9. 68. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92. 69. 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. 70. 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. 71. 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.
