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

Makoto Takeuchi,Yoshiko Kawata,Katsutoshi Oda,Takuya Ayabe,Shinya Oki,Chuwa Agapiti,Yutaka Osuga,Yuko Miyagawa,Michihiro Tanikawa,Kazunori Nagasaka,Kenbun Sone,Osamu Wada-Hiraike,Haruko Hiraike,Tomoyuki Fujii,Hiroyuki Kuramoto

doi:10.3390/cancers11121913

Makoto Takeuchi, Yoshiko Kawata + Show 13 more

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https://doi.org/10.3390/cancers11121913

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Abstract

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.

Highlights

Endometrial cancer represents the most common gynecologic malignancy in developed countries with approximately 170,000 cases diagnosed yearly, resulting in almost 36,000 deaths annually [1].Endometrial cancer is classified into two pathological types, type 1 and type2
The phosphorylation of ATM on Ser1981 and that of Chk2 on Thr68 were considered as indices of ATM activation [35,36]. γH2AX was considered as the index of DNA double2.1
The phosphorylation of ATM on Ser1981 and that of Chk2 on Thr68 were considered as indices of ATM activation [35,36]. γH2AX was considered as the index of DNA double-strand breaks, and β-actin was the control

Summary

Introduction

Endometrial cancer represents the most common gynecologic malignancy in developed countries with approximately 170,000 cases diagnosed yearly, resulting in almost 36,000 deaths annually [1].Endometrial cancer is classified into two pathological types, type 1 (estrogen-dependent) and type2 (estrogen-independent). Endometrial cancer is classified into two pathological types, type 1 (estrogen-dependent) and type. The carcinogenesis of type 1 endometrial cancer is related to a continuous exposure to estrogen, e.g., early menarche, late menopause, nulliparous, hormone replacement therapy, obesity, hypertension, and diabetes [3,4,5]. The standard treatment of endometrial cancer consists of surgery followed by radiation therapy, chemotherapy, or both, depending on the risk factors of a patient, which include muscle layer invasion, vascular invasion, grade, lymph node metastasis, and the stage of the disease [7,8,9,10]. The prognosis for recurrent cases is very poor, with a 5-year survival rate of approximately 15% because of the limited choices of treatment and resistance to therapy. Molecular-targeted therapy is expected to be the new strategy for endometrial cancer treatment [11,12]

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