Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo
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Jing Hu1,2, Xu Zhang2, Fang Wang2, Xiaokun Wang2, Ke Yang2, Meng Xu2, Kenneth K.W. To3, Qingshan Li1,*, Liwu Fu2,*
1Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
2Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Esophageal Cancer Institute, Cancer Center, Sun Yat-Sen University, Guangzhou, China
3School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
*These authors have contributed equally to this work
Liwu Fu, e-mail: [email protected]
Qingshan Li, e-mail: [email protected]
Keywords: ceritinib, multidrug resistance, ATP-binding cassette transporters, ABCB1, ABCG2
Received: June 30, 2015 Accepted: October 01, 2015 Published: November 09, 2015
Multidrug resistance (MDR) is the leading cause of treatment failure in cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, ABCC1 and ABCG2, play a key role in mediating MDR by pumping anticancer drugs out from cancer cells. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) currently in phase III clinical trial for the treatment of non-small cell lung cancer. Here, we found that ceritinib remarkably enhanced the efficacy of chemotherapeutic drugs in ABCB1 or ABCG2 over-expressing cancer cells in vitro and in vivo. Ceritinib significantly increased the intracellular accumulation of chemotherapeutic agents such as doxorubicin (DOX) by inhibiting ABCB1 or ABCG2-mediated drug efflux in the transporters-overexpressing cells. Mechanistically, ceritinib is likely a competitive inhibitor of ABCB1 and ABCG2 because it competed with [125I]-iodoarylazidoprazosin for photo affinity labeling of the transporters. On the other hand, at the transporters-inhibiting concentrations, ceritinib did not alter the expression level of ABCB1 and ABCG2, and phosphorylation status of AKT and ERK1/2. Thus the findings advocate further clinical investigation of combination chemotherapy of ceritinib and other conventional chemotherapeutic drugs in chemo-refractory cancer patients.
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