Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo

// Jing Hu 1, 2 , Xu Zhang 2 , Fang Wang 2 , Xiaokun Wang 2 , Ke Yang 2 , Meng Xu 2 , Kenneth K.W. To 3 , Qingshan Li 1, * , Liwu Fu 2, * 1 Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China 2 Collaborative 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 3 School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China * These authors have contributed equally to this work Correspondence to: Liwu Fu, e-mail: Fulw@mail.sysu.edu.cn Qingshan Li, e-mail: drliqingshang@126.com Keywords: ceritinib, multidrug resistance, ATP-binding cassette transporters, ABCB1, ABCG2 Received: June 30, 2015 Accepted: October 01, 2015 Published: November 09, 2015 ABSTRACT 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 [ 125 I]-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.