title: Pelitinib (EKB-569) targets the up-regulation of ABCB1 and ABCG2 induced by hyperthermia to eradicate lung cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Alterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization.
  
  
  RESULTS
  While pelitinib did not modulate ABCB1/ABCG2 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 ABCB1- and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells.
  
  
  CONCLUSIONS
  This study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia.
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Poon
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oncology in South China, 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 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006979:Hyperthermia, Induced; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D000634:Aminoquinolines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D019772:Topotecan; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C413879:EKB 569; C421109:multidrug resistance-associated protein 1