title: ABT-263, a Bcl-2 inhibitor, enhances the susceptibility of lung adenocarcinoma cells treated with Src inhibitors to anoikis.
abstract: The tyrosine kinase Src plays an important role in the development of anoikis resistance in lung adenocarcinomas. Several suspension lung adenocarcinoma cell lines, which express phosphorylated Src, undergo apoptosis, or anoikis, in the presence of Src kinase inhibitors. However, lung adenocarcinoma cell lines vary in their sensitivity to Src inhibitors. We hypothesized that the addition of ABT-263, a potent Bcl-2 inhibitor, should significantly enhance the degree of anoikis in lung adenocarcinoma cells treated with Src inhibitors. In this study, we treated four suspension lung adenocarcinoma cell lines with ABT-263, an Src inhibitor (bosutinib or PP1), or a combination of both. In LC-KJ and HCC827 cells, combined treatment with ABT-263 and an Src inhibitor effectively induced anoikis, and the extent of anoikis was significantly greater than that induced by each agent alone; the synergy between the two drugs was apparent. Although we did not observe a marked increase in anoikis in LC-KJ and HCC827 cells treated with ABT-263 alone, H1650 and H1975 cells treated with ABT-263 (1 μM) upon detachment significantly underwent apoptosis, the levels of which were much greater than those observed upon attachment. However, the levels of anoikis induced by combination treatment were still greater than those by the individual agents in H1650 and H1975 cells. These findings provide a biological rationale to test combination therapy with ABT-263 and Src inhibitors in patients with lung adenocarcinoma.
authors.affiliation: Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 1-1-2 Nakao, Asahi-ku, Yokohama 241-0815, Japan. ysakuma@gancen.asahi.yokohama.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Jun
authors.initials: J
authors.lastname: Tsunezumi
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Yoshihara
authors.forename: Shoichi
authors.initials: S
authors.lastname: Matsukuma
authors.forename: Shiro
authors.initials: S
authors.lastname: Koizume
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyagi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D023102:Anoikis / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016392:Proto-Oncogene Proteins pp60(c-src); C528561:navitoclax