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KCP10043F Represses the Proliferation of Human Non-Small Cell Lung Cancer Cells by Caspase-Mediated Apoptosis via STAT3 Inactivation.
Lee, Jeong-Hun; Lee, Hwi-Ho; Ryu, Ki Deok; Kim, Misong; Ko, Dohyeong; Chung, Kyung-Sook; Hassan, Ahmed H E; Lee, Seung Hyeun; Lee, Jae Yeol; Lee, Kyung-Tae.
Afiliação
  • Lee JH; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • Lee HH; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Korea.
  • Ryu KD; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • Kim M; BioCast R&D Center, 702, Eonju-ro, Gangnam-gu, Seoul 06061, Korea.
  • Ko D; Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Korea.
  • Chung KS; Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Korea.
  • Hassan AHE; Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Korea.
  • Lee SH; Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
  • Lee JY; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • Lee KT; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul 02447, Korea.
J Clin Med ; 9(3)2020 Mar 05.
Article em En | MEDLINE | ID: mdl-32150979
ABSTRACT
We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce G1-phase arrest and synergistic cell death in combination with etoposide in lung cancer cells. Here, we investigated the underlying mechanism by which KCP10043F induces cell death in non-small cell lung cancer (NSCLC). Propidium iodide (PI) and annexin V staining revealed that KCP10043F-induced cytotoxicity was caused by apoptosis. KCP10043F induced a series of intracellular events (1) downregulation of Bcl-2 and Bcl-xL and upregulation of Bax and cleaved Bid; (2) loss of mitochondrial membrane potential; (3) increase of cytochrome c release; (4) cleavage of procaspase-8, procaspase-9, procaspase-3, and poly (ADP-ribose) polymerase (PARP). In addition, KCP10043F exhibited potent inhibitory effects on constitutive or interleukin-6 (IL-6)-induced signal transducer and activator of transcription (STAT3) phosphorylation and STAT3-regulated genes including survivin, Mcl-1, and cyclin D1. Furthermore, STAT3 overexpression attenuated KCP10043F-induced apoptosis and the cleavage of caspase-9, caspase-3, and PARP. Docking analysis disclosed that KCP10043F could bind to a pocket in the SH2 domain of STAT3 and prevent STAT3 phosphorylation. The oral administration of KCP10043F decreased tumor growth in an A549 xenograft mouse model, as associated with the reduced phosphorylated STAT3, survivin, Mcl-1, and Bcl-2 expression and increased TUNEL staining and PARP cleavage in tumor tissues. Collectively, our data suggest that KCP10043F suppresses NSCLC cell growth through apoptosis induction via STAT3 inactivation.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article