ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

Vaidyanathan, Aparajitha; Sawers, Lynne; Gannon, Anne-Louise; Chakravarty, Probir; Scott, Alison; Bray, Susan E.; Ferguson, Michelle; Smith, Gillian

doi:10.1038/bjc.2016.203

Cited by 264 publications

(232 citation statements)

References 68 publications

(77 reference statements)

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“…2A left) (12). ABCB1 is a cell membrane efflux protein responsible for pumping a wide array of substrates out of cells and is known to be able to confer resistance to several chemotherapeutic drugs including docetaxel, doxorubicin, and paclitaxel (17). Whether ABCB1 mediates resistance to cabazitaxel in prostate cancer is unclear.…”

Section: Resultsmentioning

confidence: 99%

ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

Lombard

Liu

Armstrong

et al. 2017

Molecular Cancer Therapeutics

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Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations which overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small molecule inhibitor elacridar re-sensitizes taxane resistant cells to treatment. Additionally, the anti-androgens bicalutamide and enzalutamide, previously demonstrated to be able to re-sensitize taxane resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to re-sensitize resistant cells to cabazitaxel treatment. Lastly, we show that re-sensitization using an anti-androgen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in utilizing combinations of anti-androgens with cabazitaxel for increased effect in treating advanced CRPC.

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Section: Resultsmentioning

confidence: 99%

ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

Lombard

Liu

Armstrong

et al. 2017

Molecular Cancer Therapeutics

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“…Combination therapy of oxaliplatin with dasatinib, a Src inhibitor, has previously exhibited antitumor effects in a mucinous cancer model (23). Additionally, the ABC inhibitors verapamil and elacridar re-sensitized chemoresistant cells to taxanes (84). Therefore, chemotherapeutics may be combined with tyrosine kinase inhibitors or P-glycoprotein inhibitors to enhance cytotoxicity (85).…”

Section: Combination Of Cytotoxic Agents With Therapeutic Antibodies mentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

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Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

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“…2 P-glycoprotein functions as a drug-efflux pump on the surface of cancer cell to efflux taxol. 3 Other mechanisms responsible for taxol resistance include the mutations of taxol-binding protein tubulin, deregulation of cell cycle and high expression of anti-apoptotic protein. 4 …”

mentioning

confidence: 99%

Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3

Nie

et al. 2016

Cell Death Dis

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Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3′-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.

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ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

Cited by 264 publications

References 68 publications

ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3

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