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

Kim,Jong-Yun; Choi,Hye-Eun; Lee,Hwi-Ho; Shin,Ji-Sun; Shin,Dong‑Hyun; Choi,Jung-Hye; Lee,Yong Sup; Lee,Kyung-Tae

doi:10.3892/or.2015.3871

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

Authors:
- Jong-Yun Kim
- Hye-Eun Choi
- Hwi-Ho Lee
- Ji-Sun Shin
- Dong‑Hyun Shin
- Jung-Hye Choi
- Yong Sup Lee
- Kyung-Tae Lee
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Affiliations: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea, Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Hoegi-Dong, Seoul 130-701, Republic of Korea
Published online on: March 20, 2015 https://doi.org/10.3892/or.2015.3871
Pages: 2639-2647

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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.

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