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Open AccessArticle

Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells

1
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
2
Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-8605, Japan
3
Kanagawa Health Service Association, Yokohama 231-0021, Japan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(12), 1913; https://doi.org/10.3390/cancers11121913
Received: 4 November 2019 / Revised: 25 November 2019 / Accepted: 27 November 2019 / Published: 1 December 2019
(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)
: While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.
Keywords: DNA damage response (DDR) pathways; ATR-Chk1 pathway; ATM-Chk2 pathway; combination therapy; molecular-targeted therapies DNA damage response (DDR) pathways; ATR-Chk1 pathway; ATM-Chk2 pathway; combination therapy; molecular-targeted therapies
MDPI and ACS Style

Takeuchi, M.; Tanikawa, M.; Nagasaka, K.; Oda, K.; Kawata, Y.; Oki, S.; Agapiti, C.; Sone, K.; Miyagawa, Y.; Hiraike, H.; Wada-Hiraike, O.; Kuramoto, H.; Ayabe, T.; Osuga, Y.; Fujii, T. Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells. Cancers 2019, 11, 1913.

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