title: Treatment with a Small Synthetic Compound, KMU-193, induces Apoptosis in A549 Human Lung Carcinoma Cells through p53 Up-Regulation.
abstract: Despite recent advances in therapeutic strategies for lung cancer, mortality still is increasing. In the present study, we investigated the anti-cancer effects of KMU-193, 2-(4-Ethoxy-phenyl)-N-{5-[2-fluoro-4-(4-methyl- piperazine-1-carbonyl)-phenylamino]-1H-indazol-3-yl}-acetamide in a human non-small cell lung cancer cell line A549. KMU-193 strongly inhibited the proliferation of A549 cells, but it did not have anti-proliferative effect in other types of cancer cell lines. KMU-193 further induced apoptosis in association with activation of caspase-3 and cleavage of PLC-γ1. However, KMU-193 had no apoptotic effect in untransformed cells such as TMCK-1 and BEAS-2B. Interestingly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor, strongly abrogated KMU- 193-induced apoptosis. KMU-193 treatment enhanced the expression levels of p53 and PUMA. Importantly, p53 siRNA transfection attenuated KMU-193-induced apoptosis. Collectively, these results for the first time demonstrate that KMU-193 has strong apoptotic effects on A549 cells and these are largely mediated through caspase-3- and p53-dependent pathways.
authors: Department of Internal Medicine, Yeungnam University College of Medicine, South Korea E-mail : j303nih@dsmc.or.kr, god98005@dsmc.or.kr.
authors: Eun Young
authors: EY
authors: Choi
authors: Kyeong-Cheol
authors: KC
authors: Shin
authors: Jinho
authors: J
authors: Lee
authors: Taeg Kyu
authors: TK
authors: Kwon
authors: Shin
authors: S
authors: Kim
authors: Jong-Wook
authors: JW
authors: Park
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D007191:Indazoles; C000608265:KMU-193; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53