title: A novel antagonist to the inhibitors of apoptosis (IAPs) potentiates cell death in EGFR-overexpressing non-small-cell lung cancer cells.
abstract: In the effort to develop an efficient chemotherapy drug for the treatment of non-small-cell lung cancer (NSCLC), we analyzed the anti-tumorigenic effects of a novel small molecule targeting the inhibitor of apoptosis (IAPs), HM90822B, on NSCLC cells. HM90822B efficiently decreased IAP expression, especially that of XIAP and survivin, in several NSCLC cells. Interestingly, cells overexpressing epidermal growth factor receptor (EGFR) due to the mutations were more sensitive to HM90822B, undergoing cell cycle arrest and apoptosis when treated. In xenograft experiments, inoculated EGFR-overexpressing NSCLC cells showed tumor regression when treated with the inhibitor, demonstrating the chemotherapeutic potential of this agent. Mechanistically, decreased levels of EGFR, Akt and phospho-MAPKs were observed in inhibitor-treated PC-9 cells on phosphorylation array and western blotting analysis, indicating that the reagent inhibited cell growth by preventing critical cell survival signaling pathways. In addition, gene-specific knockdown studies against XIAP and/or EGFR further uncovered the involvement of Akt and MAPK pathways in HM90822B-mediated downregulation of NSCLC cell growth. Together, these results support that HM90822B is a promising candidate to be developed as lung tumor chemotherapeutics by targeting oncogenic activities of IAP together with inhibiting cell survival signaling pathways.
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: C L
authors.initials: CL
authors.lastname: Jung
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
authors.forename: I H
authors.initials: IH
authors.lastname: Bae
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Suh
authors.affiliation: Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
authors.forename: Y G
authors.initials: YG
authors.lastname: Ahn
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: D-H
authors.initials: DH
authors.lastname: Jin
authors.affiliation: 1] Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea [2] Department of Medicinal Oncology, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Y-A
authors.initials: YA
authors.lastname: Suh
authors.affiliation: 1] Institute for Innovative Cancer Research, Asan Institute for Life Science, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea [2] Department of Pathology, Seoul Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: S J
authors.initials: SJ
authors.lastname: Jang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D054852:Small Molecule Libraries; D051636:X-Linked Inhibitor of Apoptosis Protein