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: Jong-Yun Kim, Hye-Eun Choi, Hwi-Ho Lee, Ji-Sun Shin, Dong-Hyun Shin, Jung-Hye Choi, Yong Sup Lee, Kyung-Tae Lee
• Journal: Oncology reports (Oncol Rep) Vol. 33 Issue 5 Pg. 2639-47 (May 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 25812484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin B1
• Cyclin-Dependent Kinase Inhibitor p21
• Quinazolines
• Stilbenes
• TP53 protein, human
• Tumor Suppressor Protein p53
• Protein Kinases
• Checkpoint Kinase 2
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• CDC25C protein, human
• cdc25 Phosphatases
• Resveratrol

Topics

• Ataxia Telangiectasia Mutated Proteins (genetics)
• CDC2 Protein Kinase
• Carcinoma (genetics)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Division (drug effects, genetics)
• Checkpoint Kinase 1
• Checkpoint Kinase 2 (genetics)
• Cyclin B1 (genetics)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinases (genetics)
• DNA Damage (drug effects, genetics)
• Female
• G2 Phase (drug effects, genetics)
• HeLa Cells
• Humans
• Phosphorylation (drug effects, genetics)
• Protein Kinases (genetics)
• Quinazolines (pharmacology)
• Resveratrol
• Signal Transduction (drug effects, genetics)
• Stilbenes (pharmacology)
• Tumor Suppressor Protein p53 (drug effects, genetics)
• Up-Regulation (drug effects, genetics)
• Uterine Cervical Neoplasms (genetics)
• cdc25 Phosphatases (genetics)