AZD1390, an Ataxia telangiectasia mutated inhibitor, enhances cisplatin mediated apoptosis in breast cancer cells.

Abstract

Genomic instability is often caused by deficiencies in DNA damage repair pathways, making therapeutic targeting of DDR beneficial for cancer patients with specific DDR functions. ATM kinase plays a critical role in various cellular processes and its deficiency increases sensitivity to DDR-targeted agents in different cancers. Recent studies highlight ATM inhibition as a potential clinical target, with AZD1390 being a notable ATM inhibitor due to its potent and selective inhibition, ability to accumulate at DNA breaks. The study aimed to evaluate the potential anti-cancer effects of AZD1390, a key component of the DNA damage response, in breast cancer cells. The impact of the combination of AZD1390 and cisplatin on various parameters such as cell viability, proliferation, colony formation capacity, DNA damage, reactive oxygen species (ROS) levels, mitochondrial membrane potential, cell cycle progression, and cell death in breast cancer cells was evaluated using several methodologies, including WST-1 assays, real-time cell analysis, colony formation assays, comet assays, DCF-DA, MMP/JC-1 staining assays, flow cytometry along with Western blot analysis. We found that AZD1390 and cisplatin displayed synergistic antitumor effects in breast cancer cells at low doses. Addinationaly exhibited significant anti-proliferative effects in colony formation and real-time cell proliferation experiments, increasing intracellular ROS levels and mitochondrial membrane potential.The combined treatment also arrested the cell cycle at the G2-M point. Furthermore, combination of AZD1390 with cisplatin enhances its apoptotic effects in MCF-7 and MDA-MB-231 cells. These findings could aid in developing new treatments for breast cancer that exploit the genomic instability of cancer cells.