title: Effect of ceritinib (LDK378) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo.
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.
authors.affiliation: Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.|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.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.affiliation: Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; D004317:Doxorubicin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C586847:ceritinib; D017239:Paclitaxel
keywords: ABCB1; ABCG2; ATP-binding cassette transporters; ceritinib; multidrug resistance