期刊
CANCER LETTERS
卷 445, 期 -, 页码 34-44出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.01.001
关键词
Chemoresistance; Combination chemotherapy with PKC412; Drug repositioning; Modulator; P-glycoprotein
类别
资金
- Ministry of Science and Technology of Taiwan [MOST-107-2320-B-182-017]
- Chang Gung Medical Research Program [BMRPC17, CMRPD1G0112]
- Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA
- NATIONAL CANCER INSTITUTE [ZIABC010030] Funding Source: NIH RePORTER
The occurrence of multidrug resistance (MDR) associated with the overexpression of the ATP-binding cassette (ABC) protein ABCB1 in cancer cells remains a significant obstacle to successful cancer chemotherapy. Therefore, discovering modulators that are capable of inhibiting the drug efflux function or expression of ABCB1 and re-sensitizing multidrug-resistant cancer cells to anticancer agents is of great clinical importance. Regrettably, due to potential adverse events associated with drug-drug interactions and toxicity in patients, researchers have struggled to develop a synthetic inhibitor of ABCB1 that is clinically applicable to improve the effectiveness of chemotherapy. Alternatively, through drug repositioning of approved drugs, we discovered that the FMS-like tyrosine kinase-3 (FLT3) inhibitor midostaurin blocks the drug transport function of ABCB1 and re sensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic drugs. Our findings were further supported by results demonstrating that midostaurin potentiates drug-induced apoptosis in ABCB1-overexpressing cancer cells and inhibits the ATPase activity of ABCB1. Considering that midostaurin is a clinically approved anticancer agent, our findings revealed an additional action of midostaurin and that patients with multidrug-resistant tumors may benefit from a combination therapy of midostaurin with standard chemotherapy, which should be further investigated.
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