Lee, S-H; Lee, J-Y; Jung, C L; Bae, I H; Suh, K H; Ahn, Y G; Jin, D-H; Kim, T W; Suh, Y-A; Jang, S J
Cell death & disease
2014NA ; 5 ( 16 ) :e1477.
PMID : 25321484
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Lee, S-H - 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.
Lee, J-Y - 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.
Jung, C L - 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.
Bae, I H - Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
Suh, K H - Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
Ahn, Y G - Hanmi Research Center, Hanmi Pharm. Co., Ltd., Hwaseong, Gyeonggi-do, Republic of Korea.
Jin, D-H - 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.
Kim, T W - 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.
Suh, Y-A - 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.
Jang, S J - 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.
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.
Animals; Antineoplastic Agents/chemistry/*pharmacology; Apoptosis/*drug effects; Carcinoma, Non-Small-Cell Lung/metabolism/*pathology; Cell Cycle/drug effects; Cell Line, Tumor; Cell Proliferation/drug effects; Gene Knockdown Techniques; Humans; Inhibitor of Apoptosis Proteins/*antagonists & inhibitors/metabolism; Lung Neoplasms/metabolism/*pathology; MAP Kinase Signaling System/drug effects; Male; Mice, Nude; Phosphorylation/drug effects; Small Molecule Libraries/chemistry/pharmacology; X-Linked Inhibitor of Apoptosis Protein/metabolism; Xenograft Model Antitumor Assays
MESH
Animals, Antineoplastic Agents/chemistry/*pharmacology, Apoptosis/*drug effects, Carcinoma, Non-Small-Cell Lung/metabolism/*pathology, Cell Cycle/drug effects, Cell Line, Tumor, Cell Proliferation/drug effects, Gene Knockdown Techniques, Humans, Inhibitor of Apoptosis Proteins/*antagonists & inhibitors/metabolism, Lung Neoplasms/metabolism/*pathology, MAP Kinase Signaling System/drug effects, Male, Mice, Nude, Phosphorylation/drug effects, Small Molecule Libraries/chemistry/pharmacology, X-Linked Inhibitor of Apoptosis Protein/metabolism, Xenograft Model Antitumor Assays
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