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Pelitinib ( EKB ‐569) targets the up‐regulation of ABCB 1 and ABCG 2 induced by hyperthermia to eradicate lung cancer
Author(s) -
To Kenneth K W,
Poon Daniel C,
Wei Yuming,
Wang Fang,
Lin Ge,
Fu Liwu
Publication year - 2015
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.13189
Subject(s) - abcg2 , hyperthermia , cancer cell , pharmacology , atp binding cassette transporter , efflux , cancer research , population , chemistry , biology , cancer , transporter , medicine , biochemistry , paleontology , genetics , environmental health , gene
Background and Purpose Pelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up‐regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem‐like cells responsible for cancer recurrence. Experimental Approach Alterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATP ase activity of ABCB 1/ ABCG 2 and tumoursphere formation capacity of side population ( SP ) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib‐induced chemosensitization. Key Results While pelitinib did not modulate ABCB 1/ ABCG 2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB 1‐ and ABCG 2‐mediated drug effluxes were significantly inhibited by pelitinib in a concentration‐dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB 1/ ABCG 2, which is consistent with its ability to stimulate their ATP ase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up‐regulation of ABCB 1 and ABCG 2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells. Conclusions and Implications This study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem‐like cells after hyperthermia.