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

• Published in: Cancer letters 2019-03, Vol.445, p.34-44
• Main Authors: Hsiao, Sung-Han, Lusvarghi, Sabrina, Huang, Yang-Hui, Ambudkar, Suresh V., Hsu, Sheng-Chieh, Wu, Chung-Pu
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Antitumor agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B - chemistry; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Breast cancer; Cancer; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Combination chemotherapy with PKC412; Drug Repositioning; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; FDA approval; Gene Expression Regulation, Neoplastic - drug effects; HEK293 Cells; Humans; Kinases; Leukemia; Medical research; Mice; Modulator; Molecular Docking Simulation; Multidrug resistance; Multidrug resistant organisms; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; NIH 3T3 Cells; P-glycoprotein; Penicillin; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; Staurosporine - analogs & derivatives; Staurosporine - chemistry; Staurosporine - pharmacology; Toxicity; Tumors; Up-Regulation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.01.001

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. •Midostaurin, a potent inhibitor of FMS-like tyrosine kinase-3 (FLT3), inhibits the function of ABCB1.•Midostaurin re-sensitizes ABCB1-overexpressing cancer cells to chemotherapeutics.•Midostaurin enhances drug-induced apoptosis in multidrug-resistant cancer cells.•ABCB1 does not confer resistance to Midostaurin in cancer cells.•Inclusion of midostaurin in the drug treatment may benefit patients with multidrug-resistant tumors in the future.