Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance

Wang, Yijun; Zhang, Yun-Kai; Kathawala, Rishil J.; Chen, Zhe‐Sheng

doi:10.3390/cancers6041925

Cited by 54 publications

(50 citation statements)

References 149 publications

(180 reference statements)

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“…Several mechanisms for resistance to taxanes have already been reported, such as MDR, CSC-like, and EMT-related marker overexpression (9,25,31,33). The main mechanisms involved in resistance to taxanes are expression of the MDR phenotype and the alteration of their cellular target, namely the tubulin/microtubule system (11,34).…”

Section: Discussionmentioning

confidence: 99%

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

et al. 2017

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Abstract. Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxel-resistant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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Section: Discussionmentioning

confidence: 99%

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

et al. 2017

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“…Since the discovery that the overexpression of ABC transporters in cancer cells can mediate resistance to anti‐cancer drugs, research has been directed toward developing compounds that inhibit the efflux activity of ABC transporters and increase classical chemotherapy efficacy. However, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitor due to toxicity issues . It has long been postulated that the multidrug efflux transporter P‐glycoprotein (P‐gp/ABCB1/MDR1) mediates the main mechanism of resistance within cancer cells; however, we recently showed that the Hedgehog (Hh) receptor Patched, which is overexpressed in many recurrent and metastatic cancers, pumps chemotherapeutic agents such as doxorubicin (dxr) out of cancer cells thereby also contributing to chemotherapy resistance .…”

Section: Introductionmentioning

confidence: 99%

Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo

Hasanovic

Ruggiero

Jung³

et al. 2018

Intl Journal of Cancer

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One of the crucial challenges in the clinical management of cancer is the resistance to chemotherapeutics. We recently demonstrated that the Hedgehog receptor Patched, which is overexpressed in many recurrent and metastatic cancers, is a multidrug transporter for chemotherapeutic agents such as doxorubicin. The present work provides evidences that Patched is expressed in adrenocortical carcinoma (ACC) patients, and is a major player of the doxorubicin efflux and the doxorubicin resistance in the human ACC cell line H295R. We discovered that methiothepin inhibits the doxorubicin efflux activity of Patched. This drug-like molecule enhances the cytotoxic, pro-apoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells which endogenously overexpress Patched, and thereby mitigates the resistance of these cancer cells to doxorubicin. Moreover, we report that in mice the combination of methiothepin with doxorubicin prevents the development of xenografted ACC tumors more efficiently than doxorubicin alone by enhancing the accumulation of doxorubicin specifically in tumors without obvious undesirable side effects. Our results suggest that the use of an inhibitor of Patched drug efflux such as methiothepin in combination with doxorubicin could be a promising therapeutic option for adrenocortical carcinoma, and most likely also for other Patched-expressing cancers.

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“…Problems associated with high toxicity and unforeseen drug-drug interactions are also common with synthetic inhibitors. Recently, rather than developing novel inhibitors, drug repurposing (also referred to as drug repositioning) of existing therapeutic agents has become a more practical solution to overcome MDR mediated by ABC drug transporters [63]. Therefore, we chose to investigate whether small molecule targeted drugs, such as epidermal growth factor receptor (EGFR) inhibitors, could reverse MDR mediated by ABC drug transporters.…”

Section: Introductionmentioning

confidence: 99%

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Hsiao

Murakami

et al. 2017

Cancer Letters

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The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.

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Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance

Cited by 54 publications

References 149 publications

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo

Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

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