title: Resveratrol analogue (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline induces G₂/M cell cycle arrest through the activation of ATM/ATR in human cervical carcinoma HeLa cells.
abstract: Styrylquinazolines are synthetic analogues of resveratrol and have been suggested to cause anti-inflammatory activity by modulating prostaglandin E₂ (PGE₂) production. In the present study, we evaluated cytotoxic effects of various styrylquinazoline derivatives and found that (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ) most potently inhibited the proliferation of the human cervical carcinoma HeLa cells. Exploring the growth-inhibitory mechanisms of 8-ADEQ, we found that it causes a cell cycle arrest at the G₂/M phase by DNA flow cytometric analysis, which was accompanied by upregulation of cyclin B1 expression and cyclin-dependent protein kinase 1 (Cdk1) phosphorylation. In addition, we observed that 8-ADEQ causes phosphorylation of the cell division cycle 25C (Cdc25C) protein through the activation of checkpoint kinases 1 (Chk1) and Chk2, which in turn were activated via ataxia telangiectasia mutated (ATM)/ataxia telangiectasia-Rad3-related (ATR) kinases in response to the DNA damage. Furthermore, ATM/ATR inhibitor caffeine, p53- or ATM/ATR-specific siRNA significantly attenuated 8-ADEQ-induced G₂/M arrest. These results suggest that the 8-ADEQ inhibits the proliferation of human cervical cancer HeLa cells by DNA damage-mediated G₂/M cell cycle arrest. 8-ADEQ‑induced G₂/M arrest is mediated by the activation of both Chk1/2-Cdc25 and p53-p21CIP1/WAF1 via ATM/ATR pathway, and indicates that 8-ADEQ appears to have potential in the treatment of cervical cancer.
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Jong-Yun
authors: JY
authors: Kim
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Hye-Eun
authors: HE
authors: Choi
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Hwi-Ho
authors: HH
authors: Lee
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Ji-Sun
authors: JS
authors: Shin
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Dong-Hyun
authors: DH
authors: Shin
authors: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Jung-Hye
authors: JH
authors: Choi
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Yong Sup
authors: YS
authors: Lee
authors: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea.
authors: Kyung-Tae
authors: KT
authors: Lee
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D016203:CDC2 Protein Kinase; D002277:Carcinoma / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D005260:Female; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D020687:cdc25 Phosphatases / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011799:Quinazolines; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D000077185:Resveratrol