Format

Send to

Choose Destination
Cancer Lett. 2019 Mar 31;445:34-44. doi: 10.1016/j.canlet.2019.01.001. Epub 2019 Jan 11.

The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents.

Author information

1
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: johnson170_ya@hotmail.com.
2
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States. Electronic address: sabrina.lusvarghi@nih.gov.
3
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: yanghui.huang01@gmail.com.
4
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States. Electronic address: ambudkar@mail.nih.gov.
5
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: schsu@mail.cgu.edu.tw.
6
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan. Electronic address: wuchung@mail.cgu.edu.tw.

Abstract

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.

KEYWORDS:

Chemoresistance; Combination chemotherapy with PKC412; Drug repositioning; Modulator; P-glycoprotein

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center