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In vitro , in vivo and ex vivo characterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1
Author(s) -
Zhang Hui,
Patel Atish,
Ma ShaoLin,
Li Xiao Jie,
Zhang YunKai,
Yang PeiQi,
Kathawala Rishil J,
Wang YiJun,
Anreddy Nagaraju,
Fu LiWu,
Chen ZheSheng
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12889
Subject(s) - ibrutinib , in vivo , pharmacology , cytotoxicity , efflux , ex vivo , multiple drug resistance , chemistry , cancer research , biology , in vitro , leukemia , biochemistry , immunology , chronic lymphocytic leukemia , microbiology and biotechnology , antibiotics
Background and Purpose The transporter, multidrug resistance protein 1 ( MRP1 , ABCC1 ), plays a critical role in the development of multidrug resistance ( MDR ). Ibrutinib is an inhibitor of B ruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1 ‐mediated MDR . Experimental Approach Cytotoxicity was determined by MTT assay. The expression of protein was detected by W estern blot. RT‐PCR and Q‐PCR were performed to detect the expression of MRP1 mRNA . The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293 / MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo . Key Results Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293 / MRP1 and HL60 / Adr cells overexpressing MRP1 . Furthermore, ibrutinib increased the accumulation of substrates in these MRP1 ‐overexpressing cells by inhibiting the drug efflux function of MRP1 . However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1 ‐overexpressing cells. In vivo , ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293 / MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. Conclusions and Implications Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1 ‐overexpressing cells, in vitro , in vivo and ex vivo . These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1 .