SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation

Gopalakrishnan, Vidya and Sharma, Shivangi and Ray, Ujjayinee and Manjunath, Meghana and Lakshmanan, Divya and Vartak, Supriya V. and Gopinatha, Vindya K. and Srivastava, Mrinal and Kempegowda, Mantelingu and Choudhary, Bibha and Raghavan, Sathees C. (2021) SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation. Molecular Carcinogenesis, 60 (9). pp. 627-643.

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Nonhomologous end joining (NHEJ), one of the major DNA double-strand break repair pathways, plays a significant role in cancer cell proliferation and resistance to radio and chemotherapeutic agents. Previously, we had described a small molecule inhibitor, SCR7, which inhibited NHEJ in a DNA Ligase IV dependent manner. Here, we report that SCR7 potentiates the effect of gamma-radiation (IR) that induces DNA breaks as intermediates to eradicate cancer cells. Dose fractionation studies revealed that coadministration of SCR7 and IR (0.5 Gy) in mice Dalton's lymphoma (DLA) model led to a significant reduction in mice tumor cell proliferation, which was equivalent to that observed for 2 Gy dose when both solid and liquid tumor models were used. Besides, co-treatment with SCR7 and 1 Gy of IR further improved the efficacy. Notably, there was no significant change in blood parameters, kidney and liver functions upon combinatorial treatment of SCR7 and IR. Further, the co-treatment of SCR7 and IR resulted in a significant increase in unrepaired DSBs within cancer cells compared to either of the agent alone. Anatomy, histology, and other studies in tumor models confirmed the cumulative effects of both agents in activating apoptotic pathways to induce cytotoxicity by modulating DNA damage response and repair pathways. Thus, we report that SCR7 has the potential to reduce the side effects of radiotherapy by lowering its effective dose ex vivo and in mice tumor models, with implications in cancer therapy.

Item Type: Article
Uncontrolled Keywords: cancer therapy; chemotherapy; DNA ligase IV; double-strand break; end joining; homologous recombination; NHEJ; radiotherapy
Subjects: C Chemical Science > Chemistry
Divisions: Department of > Chemistry
Depositing User: Mr Umendra uom
Date Deposited: 17 May 2022 10:08
Last Modified: 17 May 2022 10:08

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