Open Access

Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein (Review)

  • Authors:
    • Xi Xia
    • Susan P.C. Cole
    • Tiange Cai
    • Yu Cai
  • View Affiliations

  • Published online on: April 3, 2017     https://doi.org/10.3892/ol.2017.5976
  • Pages: 3989-3996
  • Copyright: © Xia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Multidrug resistance (MDR) is a major cause of chemotherapy failure. It occurs when an organism is resistant to one type of drug, but also develops resistance to other drugs with different structures and targets. There is a high incidence of MDR in cancer chemotherapy, therefore, finding an effective and non‑toxic MDR reversal agent is an important goal, particularly for P-glycoprotein-mediated MDR in cancer. Improvements continue to be made to the status and understanding of traditional Chinese medicine (TCM), due to the advantages of low toxicity and relatively minor side effects. Therefore TCM is currently being used in the treatment of various types of diseases. In recent years, numerous components of TCM have been identified to be effective in reversing MDR by downregulating expression of the drug transporter membrane protein, recovering changes in enzymes involved in detoxification and metabolism and repairing the cell apoptosis pathway. The present study summarizes the anticancerous properties and MDR reversing components of traditional medicinal plants commonly used in the treatment of cancer.

Introduction

Multidrug resistance (MDR) in cancer refers to tumor cells that not only exhibit resistance to a single drug to which they have been exposed, but they also develop cross-resistance to multiple drugs with different structures, cellular targets and mechanisms of action (1,2). MDR thus reduces the sensitivity of tumor cells to cytotoxic and targeted chemotherapeutic agents, and is one reason why individuals with cancer may not respond to other effective chemotherapeutic regimens. Traditional Chinese medicine (TCM) is recognized by an increasing number of individuals for its potential applications in tumor therapy due to the advantages of its relatively low toxicity, its reported efficacy and its ability to target multiple cellular pathways. Following a comprehensive number of studies, it has been demonstrated that various components of TCM may have the potential to reverse MDR in tumors. TCM may be particularly effective in tumors in which resistance is mediated through the elevated expression of the drug transporter membrane protein, P-glycoprotein (P-gp). The present study provides a brief review of the field of TCM and P-gp.

Mechanisms of MDR

The mechanisms of MDR are multifaceted and complex, and include several factors that are summarized in Fig. 1. Among these factors are: An adenosine 5′-triphosphate (ATP) dependent decrease in cellular drug accumulation in tumor cell lines associated with elevated levels of the 170 kDa drug transporter P-gp, the 190 kDa multidrug resistance protein 1 (MRP1), or other ATP-binding cassette (ABC) drug efflux pump (35); changes in enzymes involved in detoxification and metabolism (e.g. increased levels of glutathione S-transferases and decreased topoisomerase II levels) (6); changes in DNA damage repair capacity of the tumor cells; and the dysregulation of apoptosis-related genes (7) (e.g. increased B-cell lymphoma 2, mutation of tumor protein p53 and activation of RAS). Other factors involved include changes in the tumor microenvironment in vivo, decreases in cytokine secretion and changes in hormone levels (810). Of all these factors, drug efflux mediated by P-gp is perhaps the most studied.

As mentioned, P-gp is a member of the ABC superfamily of membrane proteins, and was first identified in the plasma membrane of mammalian cells that had been selected for resistance to drugs (1,11). It is present in a number of normal tissues (12), and uses the energy from ATP binding and hydrolysis to effect the conformational changes in the protein necessary to pump xenobiotics (including anticancer drugs) across the cell membrane (13,14). Human P-gp is encoded by the ATP-binding cassette sub family B member 1 (ABCB1) gene (formerly termed MDR1), and has 1,280 amino acids that are organized in 2 homologous halves, each containing a hydrophobic transmembrane domain (TMD) with 6 transmembrane segments (TM), and a cytoplasmic nucleotide binding domain (NBD) (1,15). Substrate binding and translocation occurs largely through the TMDs, while ATP binding and hydrolysis requires the cooperation of the two NBDs (Fig. 2) (1,13,16).

P-gp as a target for reversing MDR in cancer

P-gp mediated drug efflux in tumor cells is an important resistance mechanism, and studies into MDR reversal agents almost always include this transporter protein as a target. Numerous small molecule inhibitors of P-gp have been developed during the last 4 decades (17). Verapamil was the first small molecule reported to reverse MDR mediated by P-gp in 1981 (18). The multiple P-gp MDR reversal agents described since then have been assigned to one of three generations, according to the timing of their discovery and development, and their individual features, selectivity and effectiveness. Although all MDR reversal agents possess a certain degree of effectiveness, each individual agent has shortcomings (see Table I for details).

Table I.

Selected examples of P-gp multi drug resistance reversal agents.

Table I.

Selected examples of P-gp multi drug resistance reversal agents.

GenerationRepresentative agent CharacteristicsShortcomings
1stVerapamil, cyclosporin A, auinidineCompetitive inhibitors of P-gpWeakly competitive, no target specificity, adverse side effects
2ndR-verapamil, cyclosporin A derivatives, quinidine analoguesOften structural analogs of first generation of reversal agentsAlters metabolism/pharmacokinetics of chemotherapeutic agent
3rdXR9576, LY335979, R101933, TariquidarDesigned according to structure or activity predictions; more specific, non-competitive P-gp inhibitorsMay inhibit certain P-gp pump functions in normal cells; may alter pharmacokinetics

[i] P-gp, P-glycoprotein.

The majority of small molecule reversal agents interact with P-gp at its drug binding sites through a competitive or non-competitive mechanism to inhibit the transport of anticancer drugs. Despite promising pre-clinical results in experimental systems, none have yet been approved for clinical use as reversal agents (19). Studies of certain reversal agents were terminated due to unacceptable patient toxicities in clinical trials or apparent lack of efficacy (2022). Consequently, the search for effective and less toxic tumor MDR reversal agents continues to be a target pursued by numerous studies. An increasing number of non-toxic natural plant medicines are now being studied for their potential as MDR reversal agents. A variety of TCM components have been shown to have good activity with respect to reversing tumor MDR in experimental model systems. Studies on TCM components as P-gp reversal agents have mainly been performed in vitro using cultured cells and in rat models bearing MDR tumors.

In vitro experimental studies on TCM components as P-gp reversal agents

MDR tumor cell lines with elevated P-gp levels have been used in vitro to study the effect and mechanism of TCM components on the reversal of MDR. Frequently, a colorimetric MTT chemosensitivity assay is used to determine the effect of the P-gp reversal agent on the IC50 (concentration which inhibits cell viability by 50%) of the cytotoxic drug as well as the degree of drug resistance (fold change in resistance). Changes of P-gp content and the levels of related genes are typically measured in the cells by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting, and/or flow cytometry.

Rh2 ginsenosides

Rh2 ginsenosides are mainly derived from the dry roots and leaves of Panax ginseng C.A. Meyer (Araliaceae), and are given to patients with cancer to promote immunity against cancer through enhancing immune cell activity. Different concentrations of Rh2 ginsenosides were added to cultured MDR breast cancer MCF7/ADM cells and then resistance to doxorubicin (DOX; also termed adriamycin) and 5-fluorouracil (5FU), two agents commonly used to treat breast cancer clinically, were examined (23). The Rh2 ginsenosides were also tested for their ability to influence the fluorescence intensity of MDR cells incubated in rhodamine 123 as a measure of their effect on P-gp efflux activity. The Rh2 ginsenosides increased the sensitivity of MCF7/ADM cells to DOX and 5FU. In addition, the Rh2 ginsenosides significantly inhibited the cellular efflux of rhodamine 123 from the MDR cells (23). This indicates that Rh2 ginsenosides can effectively reduce P-gp activity to reverse tumor cell MDR.

Rh2 ginsenosides perform an additional important role in leukemia and breast cancer cells. In addition to reducing P-gp activity, they have been demonstrated to decrease the levels of phospho-protein kinase B (p-AKT) and matrix metalloproteinase-2, and reduce the invasion and metastasis of MCF7/ADM cells through the suppression of the phosphoinositide 3-kinase/AKT signaling pathway (24). Rh2 ginsenosides could be excellent anti-leukemic agents due to their ability to inhibit growth, induce apoptosis and reverse the MDR of human leukemia K562/VCR cell lines (25).

Matrine

Matrine is a tetracycline quinolizidine alkaloid found mainly in members of the legume genus Sophora flavescens. Matrine has anti-inflammatory (26,27), antiviral (28), and antitumor effects (2932), and can also reverse MDR (3335). Thus, the effect of celecoxib, alone and combined with matrine, on the resistance of MDR erythroleukemia K562/AO2 cell lines was examined. Gui et al (33) revealed that in the presence of matrine, the DOX IC50 in erythroleukemia K562/AO2 cells was reduced almost 4-fold (from 33.31 to 9.44 µg/ml). The extent of apoptosis also increased from 4.81 to 15.31%. RT-PCR analyses demonstrated that ABCB1 and cyclooxygenase-2 (COX-2) mRNA levels were downregulated, as were the levels of the corresponding P-gp and COX-2 proteins. These data indicate that matrine likely reverses MDR (and enhances chemosensitivity) by reducing P-gp levels through the downregulation of ABCB1. In similarly designed studies using MDR breast cancer MCF-7/ADR (34) and hepatoma CRBH-7919/MDR1 cell lines (35), similar conclusions were reached that matrine reverses P-gp mediated MDR.

Quercetin

Quercetin is a natural flavonoid compound that exists widely in TCM, and in certain vegetables, fruits and grains. Quercetin appears to act as an MDR reversal agent through a variety of different mechanisms. For example, Wang et al (36) established a drug resistant glioma cell line (U87/TR) by exposing drug sensitive cells to temozolomide (TMZ). The authors determined that, compared with TMZ alone, the cell survival rate with a combination of quercetin with TMZ was significantly decreased (P<0.01), and cell toxicity was enhanced in a dose-dependent manner. Wang et al (37) also revealed that quercetin inhibited proliferation and enhanced apoptosis of a tamoxifen resistant breast cancer MCF-7Ca/TAM-R cell line, in a dose-dependent manner. In addition, Wang et al (38) reported that quercetin could significantly diminish P-gp activity in drug resistant lung adenocarcinoma A549/DDP cell lines and enhance the accumulation of chemotherapeutic agents. Wei et al (39) and He et al (40) also reported that quercetin resulted in a decrease in ABCB1 gene expression.

Emodin

Emodin (EM) is a type of anthraquinone extracted from rhubarb that possesses a variety of physiological activities, including inhibiting tumor cell proliferation, promoting apoptosis, and reversing MDR. EM can augment cisplatin cytotoxicity in platinum-resistant ovarian cancer COC1/DDP cells via reactive oxygen species-dependent downregulation of MRP1 (41). Li et al (42) reported that EM (10 µM) could markedly promote apoptosis in MDR human ovarian A2780/taxol tumor cells. It could also enhance the sensitivity of these cells to paclitaxel, and downregulate the intracellular levels of P-gp and inhibitor of apoptosis protein. Consequently, the authors concluded that the mechanism of EM-mediated reversal of MDR is associated with P-gp.

Tetramethylpyrazine

Tetramethylpyrazine (TMP; also termed ligustrazine) is a type of pyrazine alkaloid that occurs in the chuanqiong TCM. TMP has calcium channel blocking activity, and thus may be considered as an MDR reversal agent in tumors. The effect of TMP on P-gp activity was examined by Yu et al (43) using hepatoma BEL-7402/ADM cells. In one study, the authors examined 4 groups: BEL-7402 (drug sensitive) cells; BEL-7402/ADM (drug resistant) cells; BEL-7402/ADM cells exposed to verapamil (positive control group); and BEL-7402/ADM exposed to TMP (experimental group). Levels of P-gp were then measured by flow cytometry and immunohistochemistry. The results indicated that P-gp expression in BEL-7402/ADM cells was significantly increased compared with BEL-7402 cells, as expected. However, the authors also revealed that P-gp expression in BEL-7402/ADM cells was significantly lower following the treatment of cells with TMP (P<0.01).

Zhang et al (44) examined the effects of TMP on MDR breast cancer cells and demonstrated that TMP increased the intracellular concentration of DOX and inhibited P-gp mediated efflux of DOX in a dose-dependent manner. Additionally, TMP inhibited the ATPase activity of P-gp and suppressed the expression of P-gp in MCF-7/DOX cells.

Baicalin

Baicalin is a flavonoid compound isolated from the Scutellaria baicalensis root and is reported to demonstrate antibacterial, anti-inflammatory, anti-allergy and anticancer activity. Yang et al (45) observed that baicalin could reverse the resistance of leukemia K562/ADR cells. Thus the DOX resistance of these cells was reversed 5.2 and 19.3 fold with baicalin at 10 and 20 mg/l, respectively. Intracellular DOX accumulation was also increased significantly. The authors concluded that resistance reversal by baicalin may be associated with its ability to inhibit expression of the ABCB1 gene.

Schizandrin B

It has been reported that 5 schizandrins isolated from the Chinese herb Fructus schizandrae (FS) could reverse P-gp mediated MDR (46). Schizandrin B is the biphenyl cyclooctene lignans present at the highest levels in FS. It demonstrated effective reversal of drug resistance in bladder tumor (47), human osteosarcoma (48) and human colon cancer cells (49). Pan et al (50) has reported that Schizandrin B demonstrated MDR reversal activity in 4 MDR human tumor cell lines, which express elevated P-gp levels. These cell lines are K562/Adr, MCF-7/Adr, KBv200 and Bcap37/Adr. Through direct interaction with P-gp, Schizandrin B reduces drug efflux activity and thus completely restores the ability of the tumor cells to accumulate drugs.

5. Studies of TCM components as P-gp reversal agents in tumor-bearing rat models

TCM components can also reverse P-gp mediated MDR in vivo as demonstrated in studies conducted on tumor bearing rats (45,51). The chemosensitizing abilities of TCM components have been analyzed by studying changes in cell protein levels (5154), tumor growth (55) or survival rate of tumor-bearing rats (56). A TCM component with MDR reversing activity should show an ability to decrease resistance related protein expression levels, to inhibit tumor growth or prolong the survival rate of tumor-bearing rats.

Matrine

In addition to having MDR reversal activity in vitro as described above, matrine also has activity in intact mice. Li et al (52) emulated the clinical chemotherapy of Cisplatin/5-FU/Cytoxan (PFC) to induce resistance in S180 tumors in mice. Following 10 days of continuous lavage with matrine solution, the study obtained S180 cells from mouse ascites. The S180 cells were then analyzed by flow cytometry, and it was determined that P-gp levels and the drug target topoisomerase II were both reduced. The authors concluded that the MDR reversing activity of matrine was associated with its ability to regulate a variety of drug resistance-related macromolecules.

Cepharanthine

Cepharanthine is a type of bisbenzylisoquinoline alkaloid extracted from the radix, stem or leaves of Menispermaceae stephania. It has been reported that cepharanthine hydrochloride can downregulate the ABCB1 gene, and may activate c-Jun/c-Jun N-terminal kinases in K562/ADR cells (53). Due to the difficulty of directly analyzing intratumoral drug concentrations or P-gp changes in vivo, Han (54) established an alternative surrogate method that took advantage of the presence of P-gp in peripheral CD8+ lymphocytes. Thus, P-gp activity was measured in CD8+ peripheral lymphocytes rather than in whole tumor bearing rats. The mean fluorescence intensity (MFI) of CD8+ cells incubated with the fluorescent P-gp substrate Rhodamine123 was used as a measure of P-gp activity, and used to study the MDR reversing effect of cepharanthine hydrochloride in vivo. Different doses of cepharanthine (2.5, 5.0 and 10.0 mg/kg), verapamil (5.0 mg/kg; positive control) and saline (vehicle control) were injected in hepatoma tumor-bearing mice (Hca/Fap), which had received tail-vein injections of Rhodamine 123. The MFI was 8.6±0.4 in the absence of cepharanthine or verapamil. Following cepharanthine treatment, the MFI in CD8+ peripheral lymphocytes increased in a dose-dependent manner to 18.9±0.8, 13.1±0.8 and 11.9±0.4, respectively; following treatment with verapamil, the MFI was 10.2±0.2. The differences among the groups were statistically significant (P<0.05), indicating that cepharanthine can reverse MDR by inhibiting the P-gp activity.

Curcumin

In a study by Lu et al (55), human colon tumor HCT-8/VCR cells were implanted in nude mice to establish MDR tumor-bearing mice. The mice were then divided into 4 groups, and administered saline (vehicle control), vincristine (VCR) alone, curcumin alone, and VCR + curcumin together, respectively. The tumors were excised and weighed following 2 weeks of treatment, and RT-PCR and immunoblotting were used to detect levels of ABC1 and survivin mRNAs as well as P-gp and survivin proteins in tumor tissue, respectively. The tumor mass and levels of ABCB1 mRNA, survivin mRNA and P-gp and survivin proteins in the VCR/curcumin combination group and the curcumin alone group were significantly lower than the control (saline) group and VCR alone group, indicating that curcumin is more effective than VCR in MDR. Other studies have also shown that curcumin could inhibit the migration and invasion of Hca-F cells (57), and induce apoptosis in gallbladder carcinoma GBC-SD cells (58).

Other TCM components

Diallyltrisulfide could overcome P-gp-mediated MDR in K562/A02 cells by the downregulation of nuclear factor-κB (NF-κB)/p65 (59). In addition, grape seed procyanidin (GSP) belongs to a class of polyphenol flavonoid compounds that significantly increase the efficacy of paclitaxel and adriamycin in A2780/T cells by blocking the function of P-gp and inhibiting the transcription of ABCB1. Additionally, GSP suppressed the NF-kB activity and mitogen activated protein kinase (MAPK)/extracellular signal-related kinases (ERK) pathway mediated YB-1 nuclear translocation, which may be associated with the downregulation of P-gp (60).

Annonaceous acetogenins can also reverse MDR by reducing P-gp pump function and increasing the intracellular concentration of chemotherapeutic drugs. Thus, 15 annonaceous acetogenins demonstrated significant inhibitory activities against MCF-7/ADR cells; among them, annotemoyin-1 was 190X more active than verapamil (61).

Tetrandrine also significantly reduced P-gp expression in a concentration-dependent manner, and thus can reverse MDR by increasing the intracellular concentration of anticancer drugs (62,63). In addition, the study demonstrated that H1 (a novel derivative of tetrandrine) inhibited P-gp expression in a dose-dependent manner by promoting P-gp degradation apparently through decreasing its half-life, which may be associated with a downregulated MAPK-ERK signaling pathway. H1 also inhibited the ATPase activity of P-gp in a dose-dependent manner (64). Psoralen (65), neferine (66,67), peimine (68,69), guggulsterone (69,70) and artemisinin (71) are also reported to reverse MDR by reducing P-gp expression or promoting the ATPase activity of P-gp in drug-resistant tumor cells (for details of TCM components, see Table II).

Table II.

Physicochemical characteristics of selected TCM components.

Table II.

Physicochemical characteristics of selected TCM components.

TCM componentMain sourceFormulaMWtStructure
Rh2 ginsenosidesPanax ginseng C36H62O8622ol-13-06-3989-g02.tif
MatrineSophora flavescens C15H24N2O248ol-13-06-3989-g03.tif
QuercetinNumerous vegetables, fruits and grain C15H10O7302ol-13-06-3989-g04.tif
EmodinRheum rhabarbarum C15H10O5270ol-13-06-3989-g05.tif
Tetramethylpyrazine HClLigusticum wallichii C8H12N2·HCl172.5ol-13-06-3989-g06.tif
BaicalinScutellaria baicalensis C21H18O11446ol-13-06-3989-g07.tif
Schizandrin BSchisandra chinensis C23H28O6400ol-13-06-3989-g08.tif
CepharanthineRheum rhabarbarum C37H38N2O6606ol-13-06-3989-g09.tif
CurcuminPolygonum cuspidatum, and Rheum rhabarbarum C21H20O6368ol-13-06-3989-g10.tif
DiallyltrisulfideAllium sativum C6H10S2O162ol-13-06-3989-g11.tif
TetrandrineStephania tetrandra C38H42N2O6622ol-13-06-3989-g12.tif
PsoralenPsoralea corylifolia C11H6O3186ol-13-06-3989-g13.tif
NeferineNelumbo nucifera C38H44N2O6624ol-13-06-3989-g14.tif
PeimineFritillaria thunbergii C27H45NO3431ol-13-06-3989-g15.tif
ArtemisininArtemisia annua C15H22O5282ol-13-06-3989-g16.tif

[i] TCM, traditional Chinese medicine; MWt, molecular weight.

Conclusions

Reversing MDR in cancer is a challenging task, and over the past several decades (72,73), a number of studies have proposed numerous strategies to combat it and 4 generations of small molecule MDR P-gp inhibitors have been reported (17). Among these are a variety of TCM components that have been shown to reverse P-gp mediated MDR by several mechanisms including inhibiting P-gp drug efflux activity, hindering P-gp ATPase activity and reducing P-gp levels by downregulating the expression levels of the ABCB1 gene. Despite these interesting observations, there are still a number of challenges that need to be addressed. Firstly, MDR is the result of numerous biochemical and cellular factors. Therefore, if studies remain narrowly focused on the classical resistance mechanism mediated by P-gp (i.e. a single target), the contributions of other resistance mechanisms will remain unexplored. Secondly, studies to date have mostly used cultured MDR tumor cell model systems. By contrast, studies utilizing tumor-bearing animals are relatively rare, and clinical studies with human patients even rarer. In addition, the majority of studies use TCM components in their purified forms, and studies of TCM components in relevant and appropriate formulations should also be examined.

To date, no single compound (or combination of compounds) has been used as a MDR reversal agent successfully in the clinic. However, as TCM components with higher efficacy and lower toxicity, and with confirmed MDR reversing mechanisms are identified, it remains a promising prospect. Additional studies are also required to explore the influence of TCM components on pharmacokinetic processes in vitro and in vivo in order to choose the optimal formulation and dosage for clinical cancer treatment.

Acknowledgements

The present work was supported in part by The National Natural Science Foundation of China (grant nos. 81273707 and 81173215), The Ministry of Education in the New Century Excellent Talents (grant no. NECT-12-0677), the Natural Science Foundation of Guangdong (grant no. S2013010012880), the Science and Technology Program of Guangzhou (grant no. 2014J4500005), the Science Program of Department of Education of Guangdong (grant nos. 2013KJCX0021 and 2015KGJHZ012) and the Science and Technology Program of Guangdong (grant no. 2015A050502027).

Glossary

Abbreviations

Abbreviations:

MDR

multidrug resistance

TCM

traditional Chinese medicine

P-gp

P-glycoprotein

MRP1

multidrug resistance protein 1

TMD

transmembrane domain

TM

transmembrane segment

NBD

nucleotide binding domain

References

1 

Gottesman MM and Ling V: The molecular basis of multidrug resistance in cancer: The early years of P-glycoprotein research. FEBS Lett. 580:998–1009. 2006. View Article : Google Scholar : PubMed/NCBI

2 

Choi CH: ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 5:302005. View Article : Google Scholar : PubMed/NCBI

3 

Leslie EM, Deeley RG and Cole SP: Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 204:216–237. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Cole SP: Targeting multidrug resistance protein 1 (MRP1, ABCC1): Past, present, and future. Annu Rev Pharmacol Toxicol. 54:95–117. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Sharom FJ: ABC multidrug transporters: Structure, function and role in chemoresistance. Pharmacogenomics. 9:105–127. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Chikamori K, Grozav AG, Kozuki T, Grabowski D, Ganapathi R and Ganapathi MK: DNA topoisomerase II enzymes as molecular targets for cancer chemotherapy. Curr Cancer Drug Targets. 10:758–771. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Kartal-Yandim M, Adan-Gokbulut A and Baran Y: Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol. 36:716–726. 2016.PubMed/NCBI

8 

Ren SX: The potential of Chinese herb on multidrug resistance. Pharmacy Clinics Chinese Materia Med. 3:57–60. 2012.

9 

Liao SL and Wang P: Research progress on multidrug resistance mechanism of cancer cells and its reversal agents. Guowai Yiyao Kangshengsu Fence. 1:7–11. 2008.(In Chinese).

10 

Pan GD and Yan L: Advances in gene therapy of multidrug resistance reversal induced by Mdr1. Huaxi Yixue. 22:205–207. 2007.(In Chinese).

11 

Sharom FJ: The P-glycoprotein multidrug transporter. Essays Biochem. 50:161–178. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Cascorbi I: P-glycoprotein: Tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol. 261–283. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Jones PM and George AM: Mechanism of the ABC transporter ATPase domains: Catalytic models and the biochemical and biophysical record. Crit Rev Biochem Mol Biol. 48:39–50. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Ward AB, Szewczyk P, Grimard V, Lee CW, Martinez L, Doshi R, Caya A, Villaluz M, Pardon E, Cregger C, et al: Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc Natl Acad Sci USA. 110:13386–13391. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Ueda K, Cornwell MM, Gottesman MM, Pastan I, Roninson IB, Ling V and Riordan JR: The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem Biophys Res Commun. 141:956–962. 1986. View Article : Google Scholar : PubMed/NCBI

16 

Loo TW and Clarke DM: Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. J Membr Biol. 206:173–185. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Crowley E, McDevitt CA and Callaghan R: Generating inhibitors of P-glycoprotein: Where to, now? Methods Mol Biol. 596:405–432. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Tsuruo T, Iida H, Tsukagoshi S and Sakurai Y: Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced toxicity of vincristine and vinblastine by verapamil. Cancer Res. 41:1967–1972. 1981.PubMed/NCBI

19 

Tamaki A, Ierano C, Szakacs G, Robey RW and Bates SE: The controversial role of ABC transporters in clinical oncology. Essays Biochem. 50:209–232. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Huang SC, Xu J and Cai SH: Research progress of targeted reverse MDR mediated by P-glycoprotein. Huaxi Yaoxue Zazhi. 24:551–554. 2009.(In Chinese).

21 

Shen XL, Hu YJ, Yu ZL and Fong WF: Research progress on reversal of multidrug resistance of P-glycoprotein mediated by Chinese Herbs. Chinese J Natural Med. 7:465–475. 2009. View Article : Google Scholar

22 

Pusztai L, Wagner P, Ibrahim N, Rivera E, Theriault R, Booser D, Symmans FW, Wong F, Blumenschein G, Fleming DR, et al: Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy resistant, advanced breast carcinoma. Cancer. 104:682–691. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Li P and Chen S: Study of the ginsenoside Rh2 reversal MCF-7/ADM multidrug resistance. Guide Chin Med. 11:8–10. 2013.(In Chinese).

24 

Piao L, Cai Y, Zhang M, Jiang J, Jin Z and Xu Z: Effects of gensenoside Rh2 combined with PI3K/AKT pathway inhibitor LY294002 on invasion and migration of breast cancer cells. China Pharmacy. 24:4050–4052. 2013.

25 

Xu X, Shi S, Tang Y, Shen H and Qian B: Therapeutic effects of ginsenoside Rh2 on multi-drug resistant leukemia cell line K562/VCR. Chin Trad Herbal Drugs. 41:1131–1135. 2010.(In Chinese).

26 

Zhang B, Liu ZY, Li YY, Luo Y, Liu ML, Dong HY, Wang YX, Liu Y, Zhao PT, Jin FG and Li ZC: Antiinflammatory effects of matrine in LPS-induced acute lung injury in mice. Eur J Pharm Sci. 44:573–579. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Zhaowu Z, Xiaoli W, Yangde Z and Nianfeng L: Preparation of matrine ethosome, its percutaneous permeation in vitro and anti-inflammatory activity in vivo in rats. J Liposome Res. 19:155–162. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Yang Y, Xiu J, Zhang X, Zhang L, Yan K, Qin C and Liu J: Antiviral effect of matrine against human enterovirus 71. Molecules. 17:10370–10376. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Li LQ, Li XL, Wang L, Du WJ, Guo R, Liang HH, Liu X, Liang DS, Lu YJ, Shan HL and Jiang HC: Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells. Cell Physiol Biochem. 30:631–641. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Jin H, Sun Y, Wang S and Cheng X: Matrine activates PTEN to induce growth inhibition and apoptosis in V600EBRAF harboring melanoma cells. Int J Mol Sci. 14:16040–16057. 2013. View Article : Google Scholar : PubMed/NCBI

31 

Zhang S, Zhang Y, Zhuang Y, Wang J, Ye J, Zhang S, Wu J, Yu K and Han Y: Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation. PLoS One. 7:e468532012. View Article : Google Scholar : PubMed/NCBI

32 

Yan F, Liu Y and Wang W: Matrine inhibited the growth of rat osteosarcoma UMR-108 cells by inducing apoptosis in a mitochondrial-caspase-dependent pathway. Tumour Biol. 34:2135–2140. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Gui L, Li J, Chen B, Gao F, Wang J and Cai X: Effect of COX-2 inhibitor celecoxib, matrine and combination on multidrug resistance of K562/AO2 cell line. J Southeast Univ (Med Sci Edi). 31:174–178. 2012.

34 

Wei C, Shen Y, Zhang Z, Wang J and Zhou B: Matrine reverses multidrug resistance in breast cancer drug-resistant cell line MCF-7/ADR through inhibiting PI3K/AKT signal pathway. J Third Mil Med Univ. 36:2254–2258. 2014.

35 

Zhan T: Matrine induces apoptosis of multidrug resistant CRBH-7919/mdr1 cells. Jilin Univ 1–84. 2012.(In Chinese).

36 

Wang J, Wang G and Liu M: Effects of quercetin on reversion of temozolomide resistance in U87/TR cell line. Yiyao Dao Bao. 32:710–714. 2013.(In Chinese).

37 

Wang H, Zhang H, Tao L, et al: Quercetin-induced strengthening efficiency to tamoxifen in tamoxifen-resistant breast cancer cells. Chin J Modern Med. 24:39–44. 2014.(In Chinese).

38 

Wang Y, Liu Z, Zhang Q, Gao X, Zhang L and Liu H: Effect of quercetin on multidrug resistance reversal of lung adenocarcinoma cell line A549/DDP. J Binzhou Med Univ. 26:86–89. 2013.

39 

Wei Y, Zhang H and Liang G: The reverse effect of quercetin on multidrug resistance of human hepatocellular carcinoma. Tianjin Med J. 40:1022–1025. 2013.

40 

He HL, Ji LJ, Li QZ, Zhang R, Huang JM and Li G: Effect of quercetin on doxorubicin-induced expression of MDR1 gene in HL-60 cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 23:70–76. 2015.(In Chinese). PubMed/NCBI

41 

Ma J, Yang J and Shen H: The chemotherapy sensitivity analysis of the impact of reactive oxygen species on ovarian cancer cells COC1 and COC1/DDP. Biol Med Res Intl. 30:535–539. 2014.(In Chinese).

42 

Li J, Liu P, Mao H, Wanga A and Zhang X: Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro. Oncol Rep. 21:1605–1610. 2009.PubMed/NCBI

43 

Yu X, Wang S, Cao Y, Mo C, Li X and Li M: Effects of tetramethylpyrazine on P-glycoprotein in human drug resistant hepatocellular carcinoma cells BEL-7402/ADM. J Guangdong Pharmaceut Coll. 26:635–639. 2010.(In Chinese).

44 

Zhang Y, Liu X, Zuo T, Liu Y and Zhang JH: Tetramethylpyrazine reverses multidrug resistance in breast cancer cells through regulating the expression and function of P-glycoprotein. Med Oncol. 29:534–538. 2012. View Article : Google Scholar : PubMed/NCBI

45 

Yang L, Zhao T, Bai Q and Dong H: Reversal effect and mechanism induced by baicalin on leukemia cell line. Shaxi Yixue Zazhi. 7:775–779. 2012.(In Chinese).

46 

Huang M, Jin J, Sun H and Liu GT: Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae. Cancer Chemother Pharmacol. 62:1015–1026. 2008. View Article : Google Scholar : PubMed/NCBI

47 

Wang M, Liu H, Yan M and Liu Z: Reversal effect of SchB on bladder tumor multidrug resistance. Natl Med Front Chin. 5:28–29. 2010.(In Chinese).

48 

Li QP and Gai YN: Schisandrin B reverses multidrug resistance due to MDR1-mediatied human osteosarcoma cell line U-2 OS/ADR. Anhui Med Pharmaceut J. 18:1642–1645. 2014.

49 

Xu Q, Jin X, Guo R, Zhang X and Liu G: Schisandrin B reverses multidrug resistance of human colon cancer cells. Food Nutr Chin. 17:64–66. 2011.(In Chinese).

50 

Qiangrong P, Wang T, Lu Q and Hu X: Schisandrin B-a novel inhibitor of P-glycoprotein. Biochem Biophys Res Commun. 335:406–411. 2005. View Article : Google Scholar : PubMed/NCBI

51 

He JB, Liao HZ, Zhang YQ, et al: Reversal effect of ginsenoside Rg3 on multidrug resistance of lung adenocarcinoma in mice. J Practical Oncol. 4:373–377. 2006.(In Chinese).

52 

Li G, Wang M, Sun F, Wang X, Li X and Yin G: Reversal effect of multidrug resistance associated gene overexpression mediated induced by matrine on S180-tumor-bearing mice. J Chin Med Mater. 29:40–42. 2006.(In Chinese).

53 

Han L, Wang Y, Guo X, Zhou Y, Zhang J, Wang N, Jiang J, Ma F and Wang Q: Downregulation of MDR1 gene by cepharanthine hydrochloride is related to the activation of c-Jun/JNK in K562/ADR cells. Biomed Res Int. 2014:1643912014. View Article : Google Scholar : PubMed/NCBI

54 

Han L: The multidrug resistance reversal effect of cepharanthine hydrochloride and its mechanism. Zhengzhou: Zhengzhou Univ 1–119. 2013.(In Chinese).

55 

Lu W, Fu Z, Qin Y, Li L and Yang C: Curcumin reverses multidrug resistance in HCT-8/VCR nude mice xenograft. Di San Jun Yi Da Xue Xue Bao Bian Ji Bu. 33:376–380. 2011.(In Chinese).

56 

Xu DH: Overcome multidrug resistance by doxorubicin nanocarriers. Zhejiang Univ 1–153. 2008.(In Chinese).

57 

Wang S, Yu S, Shi W, Ge L, Yu X, Fan J and Zhang J: Curcumin inhibits the migration and invasion of mouse hepatoma Hca-F cells through down-regulating caveolin-1 expression and epidermal growth factor receptor signaling. IUBMB Life. 63:775–782. 2011. View Article : Google Scholar : PubMed/NCBI

58 

Liu TY, Tan ZJ, Jiang L, Gu JF, Wu XS, Cao Y, Li ML, Wu KJ and Liu YB: Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells. Cancer Cell Int. 13:642013. View Article : Google Scholar : PubMed/NCBI

59 

Xia Q, Wang ZY, Li HQ, Diao YT, Li XL, Cui J, Chen XL and Li H: Reversion of P-glycoprotein mediated multidrug resistance in human leukemic cell line by diallyl trisulfide. Evid Based Complement Alternat Med. 2012:7198052012. View Article : Google Scholar : PubMed/NCBI

60 

Zhao B: Molecular mechanisms of multi-drug resistance reversal via inhibition of P-glycoprotein function and expression by Grape seed procyanidin. Guangdong: Southern Medical Univ 1–210. 2014.(In Chinese).

61 

Yuan F, Bai G, Miao YJ, Chen Y, Chen JW and Li X: Effects of annonaceous acetogenins against multidrug resistant human breast cancer cell line MCF-7/ADR in vitro. Chin Trad Herbal Drugs. 45:2815–2819. 2014.

62 

Sun YF and Wink M: Tetrandrine and fangchinoline, bisbenzylisoquinoline alkaloids from Stephania tetrandracan reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells. Phytomedicine. 21:1110–1119. 2014. View Article : Google Scholar : PubMed/NCBI

63 

Susa M, Choy E, Yang C, Schwab J, Mankin H, Hornicek F and Duan Z: Multidrug resistance reversal agent, NSC77037, identified with a cell-based screening assay. J Biomol Screen. 15:287–296. 2010. View Article : Google Scholar : PubMed/NCBI

64 

Wei N, Sun H, Wang F and Liu G: H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein. Cancer Chemother Pharmacol. 67:1017–1025. 2011. View Article : Google Scholar : PubMed/NCBI

65 

Cai Y and Cai T: Reversal effect of psoralen on leukemia cell K562/ADR multidrug resistance. Zhongguo Yaolixue Tongbao. 1164–1166. 2003.(In Chinese).

66 

Qing Q, Xiao X and Xie Z: Effect of neferine combined with mdr-1shRNA on the expression of mdr-1/P-gp in K562/A02 cell line. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 35:445–450. 2010.(In Chinese). PubMed/NCBI

67 

Huang C, Cao P, Xie Z and Zhu H: Effect of different heating methods combined with neferine on the expressions of γH2AX and mdr-1/P-gp in MCF-7/Adr breast cancer cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 36:317–322. 2011.(In Chinese). PubMed/NCBI

68 

Li Z, An C, Hu K, Zhou K, Duan H and Tang M: Multidrug resistance reversal activity of total alkaloid from Fritillaria thunbergii on cisplatin-resistant human lung adenocarcinoma A549/DDP cells. Chin J Pharmacol Toxicol. 27:315–320. 2013.

69 

Xu HB, Li L and Liu GQ: Reversal of P-glycoprotein-mediated multidrug resistance by guggulsterone in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Pharmazie. 64:660–665. 2009.PubMed/NCBI

70 

Xu HB, Xu LZ, Li L, Fu J and Mao XP: Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines. Eur J Pharmacol. 694:39–44. 2012. View Article : Google Scholar : PubMed/NCBI

71 

Yu H, Cui L and Pan Y: Reversal of drug resistance in multidrug-resistant MCF-7/ADR cells of breast cancer by artemisinin. Acta Med Univ Sci Technol Huazhong. 40:91–94. 2011.(In Chinese).

72 

Liao K, Niu F, Hao H and Wang G: Advances on structure-activity relationship of NQO1-target antitumor quinones. Chin J Nat Med. 10:170–176. 2012. View Article : Google Scholar

73 

Liao SG, Wang Z, Li J, Liu Y, Li YT, Zhang LJ, Long QD and Wang YL: Cytotoxic sesquiterpene lactones from Vernonia bockiana. Chin J Nat Med. 10:230–233. 2012. View Article : Google Scholar

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June-2017
Volume 13 Issue 6

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Spandidos Publications style
Xia X, Cole SP, Cai T and Cai Y: Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein (Review). Oncol Lett 13: 3989-3996, 2017
APA
Xia, X., Cole, S.P., Cai, T., & Cai, Y. (2017). Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein (Review). Oncology Letters, 13, 3989-3996. https://doi.org/10.3892/ol.2017.5976
MLA
Xia, X., Cole, S. P., Cai, T., Cai, Y."Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein (Review)". Oncology Letters 13.6 (2017): 3989-3996.
Chicago
Xia, X., Cole, S. P., Cai, T., Cai, Y."Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein (Review)". Oncology Letters 13, no. 6 (2017): 3989-3996. https://doi.org/10.3892/ol.2017.5976