The Chk1 inhibitor AZD7762 sensitises p53 mutant breast cancer cells to radiation in vitro and in vivo.

Abstract

AZD7762, a novel checkpoint kinase 1 (Chk 1)inhibitor, has been proven to sensitize various tumor cells to DNA damage. However, whether or not AZD7762 sensitizes breast cancer cells to radiation has not been defined. In the present study, we aimed to demonstrate for the first time, that AZD7762 not only promotes radiation-induced apoptosis and mitotic catastrophe of p53 mutant T47D breast cancer cells in vitro, but also delays their xenograft growth in response to radiation in vivo. Our mechanistic study showed that AZD7762 treatment resulted in the abrogation of radiation-induced G2/M arrest and the inhibition of radiation damage repair as demonstrated by increased radiation-induced γH2AX expression and decreased RAD51 protein expression. These results suggest that AZD7762 may effectively abrogate radiation-induced G2/M arrest and inhibit radiation damage repair in conferring radiosensitivity on p53 mutant T47D breast cancer cells, by promoting radiation-induced apoptosis and mitotic catastrophe. The clinical application of AZD7762, as an adjuvant in the radiotherapy of breast cancers, should be further explored.

• Authors: Zhikun Ma, Guoliang Yao, Bo Zhou, Yonggang Fan, Shegan Gao, Xiaoshan Feng
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 6 Issue 4 Pg. 897-903 (Oct 2012) ISSN: 1791-3004 [Electronic] Greece
• PMID: 22825736 (Publication Type: Journal Article)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Protein Kinase Inhibitors
• Radiation-Sensitizing Agents
• Thiophenes
• Tumor Suppressor Protein p53
• Urea
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Checkpoint Kinase 1
• DNA Damage (drug effects, radiation effects)
• Female
• G2 Phase Cell Cycle Checkpoints
• Gamma Rays
• Humans
• M Phase Cell Cycle Checkpoints
• MCF-7 Cells
• Mice
• Mice, Nude
• Mutation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Kinases (chemistry, metabolism)
• Radiation-Sensitizing Agents (pharmacology, therapeutic use)
• Thiophenes (pharmacology, therapeutic use)
• Transplantation, Heterologous
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Urea (analogs & derivatives, pharmacology, therapeutic use)