Ro 90-7501 Is a Novel Radiosensitizer for Cervical Cancer Cells that Inhibits ATM Phosphorylation

Abstract

Background/Aim: Ro 90-7501 has been reported as an inhibitor of the amyloid β42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. Materials and Methods: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. Results: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. Conclusion: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.Cervical cancer is one of the most common cancers among women worldwide, accounting for 569,847 new cases and 311,365 deaths annually (1). Radiotherapy has been commonly used in cervical cancer treatment for a long time, especially for locally advanced cancer. However, because treatment results are not satisfactory, development of radiosensitizers is one of the strategies to improve efficacy of radiotherapy. Although cisplatin is used as a radiosensitizer for locally advanced cervical cancer, patients often develop hematologic and gastrointestinal complications (2). Discovery for new radiosensitizers that are less toxic and more effective against cancer could improve treatment efficacy. In this study, we focused on the compound "Ro 90-7501", which is reported to be an inhibitor of amyloid β42 fibril assembly involved in Alzheimer's disease (3).Ataxia telangiectasia is caused by loss of ataxia telangiectasia mutated (ATM) function and is characterized by increased radiosensitivity (4). The ATM protein kinase is known as a tumor suppressor, which is frequently mutated in human cancers. ATM regulates cellular response to DNA double-strand breaks by phosphorylating various proteins such as Chk1, Chk2, and H2AX involved in DNA damage response and cell-cycle checkpoint activation after irradiation (5). Inhibition of DNA damage response can be effective in enhancing cytotoxicity after irradiation (6). In this context, the present study aimed to elucidate the effects of radiosensitization of Ro 90-7501 on DNA damage response through ATM signaling. Materials and MethodsCell culture. The human cervical cancer cell lines HeLa and ME-180 were purchased from American Type Culture Collection (VA, USA) and were cultured in Dulbecco's modified eagle's medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml streptomycin. Ro 90-7501 was purchased from Sigma (MO, USA) and dissolved in DMSO.Irradiation. Cells were irradiated under ambient conditions using a ceasium-137 ga...

Hyperoxia sensitizes hypoxic HeLa cells to ionizing radiation by downregulating HIF‑1α and VEGF expression

“…It has been proposed that hypoxic tumor cells achieve RR more easily compared with those in a normoxic environment, and therefore, tumor hypoxia has been associated with poor survival outcomes (6,7). Although the application of novel radiosensitizers, including Ro 90-7501, cisplatin (or nedaplatin) and curcumin, have enhanced the radiotherapy efficacy of cervical cancer (8)(9)(10)(11), the toxic effects, such as acute hematological and gastrointestinal toxicity, induced by these chemicals are difficult to avoid.…”

Synergistic inhibition of APE1 redox activity and ATM activation sensitizes osteosarcoma cells to ionizing radiation by inducing ferroptosis

“…Therefore, after IR exposure, the inhibition of APE1 redox activity might not block the functions of DNA damage-activated ATM, which thereby compensates for the effects of APE1 redox inhibition and ATM activation inhibition induced by APX3330. It also explains why APX3330 effectively sensitized OS cells to IR only when used in combination with Ro 90-7501, which has been shown to sensitize cervical cancer cells to irradiation by inhibiting the DNA damage response of ATM 55 . Conversely, the effects of ATM inhibition by Ro 90-7051 could be compensated by APE1, considering their common TFs, as mentioned above.…”

Molecular mechanisms of long noncoding RNAs associated with cervical cancer radiosensitivity

“…Both ETP-46464 and KU55933 could enhance the response to IR by affecting the expression levels of p-ATM/P-Chk1 and p-ATM/P-Chk2. A compound named Ro 90-7501 can enhance the adiosensitivity of cervical cancer by inhibiting ATM ( Tamari et al, 2019 ), A Chinese herbal medicine Osthole can also inhibited phosphorylation of ATM and enhances irradiation sensitivity of cervical cancer cells ( Che et al, 2018 ).…”