Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance

Zhou, Ying; Hopper-Borge, Elizabeth; Shen, Tong; Huang, Xiaocong; Shi, Zhi; Kuang, Yehong; Furukawa, Tatsuhiko; Akiyama, Shin-ichi; Peng, Xing-Xiang; Ashby, Charles R.; Chen, Xiang; Kruh, Gary D.; Chen, Zhe‐Sheng

doi:10.1016/j.bcp.2008.12.005

Cited by 68 publications

(65 citation statements)

References 29 publications

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“…We previously reported that cotreatment of cepharanthine with doxorubicin and vincristine resulted in the enhancement of cytotoxicity the anti-cancer drugs and the apoptosis induced in K562 cells (15). Cepharanthine also reversed paclitaxel resistance in MRP7-transfected cells (7). Therefore, we examined the effect of the sensitivity to gemcitabine in A549/GR cells.…”

Section: Discussionmentioning

confidence: 95%

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Ikeda

Vermeulen²,

Lau³

et al. 2011

Int J Oncol

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Abstract.Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabineresistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/GR cells were resistant to gemcitabine as well as paclitaxel and docetaxel but not carboplatin and irinotecan. The expression level of multidrug resistance protein 7 (MRP7) in A549/GR cells was higher than that in A549 cells, and the inhibitor of MRP7 by cepharanthine increased the sensitivity to gemcitabine in A549/GR cells. These findings indicate that cepharanthine reversed gemcitabine resistance. To determine predictive molecular markers of gemcitabine resistance for more effective treatment of these tumors, we performed PCR array. We identified that CDKN1A/p21, CYP3A5, microsomal epoxide hyrolase 1 (EPHX1) and ABCC6 (MRP6) were up-regulated >5-fold in A549/GR cells. Gemcitabine also induced the expression of p21 and CYP3A5 in A549 cells. A better understanding of the characterization and mechanism of the resistance to gemcitabine in A549/GR cells may help identify agents that reverse clinical gemcitabine resistance in NSCLC.

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Section: Discussionmentioning

confidence: 95%

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Ikeda

Vermeulen²,

Lau³

et al. 2011

Int J Oncol

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“…SiRNA study and in vivo MRP7 knockout null mouse model also confirmed that MRP7 conferred paclitaxel resistance (74). Cepharanthine is the earliest discovered MRP7 inhibitor (75), and more recent approaches towards MRP7 inhibition will be discussed in section 4.…”

Section: Mrp7mentioning

confidence: 91%

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Zhang

Wang

Gupta

et al. 2015

AAPS J

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159

114

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Abstract. The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed.

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“…Tumor cells resistant to docetaxel can exhibit an increased expression of MDR1 and MRP7, the only 2 known ABC transporters capable of transporting this drug (24). The overexpression of mrp7 has been shown in taxane-resistant patient tumors such as lung cancer (25). Because docetaxel acts by stabilizing microtubules via binding to b-tubulin subunits, the abnormal expression of certain b-tubulin isotypes or proteins such as stathmin1 hinders drug binding to its target (23,26).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Souza

Zahedi

Badame

et al. 2011

Molecular Cancer Therapeutics

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Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1Â/wk or 3Â/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including b-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1Â/wk or 3Â/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3Â/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer.

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Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance

Cited by 68 publications

References 29 publications

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

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