Japanese apricot extract (MK615) potentiates bendamustine-induced apoptosis via impairment of the DNA damage response in lymphoma cells

Abstract
Bendamustine, a hybrid molecule combining a purine analog with an alkylator, triggers cell death through apoptosis activation and DNA damage response. MK615, derived from Japanese apricot, contains cyclic triterpenes with antitumor properties. This study explored the combined effects of bendamustine and MK615 on lymphoma cells. The results showed that the two agents worked synergistically to induce apoptosis in all lymphoid cell lines tested. MK615 was found to inhibit the bendamustine-induced phosphorylation of checkpoint kinase 1 and 2. Given that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) kinases play crucial roles in the DNA damage response, the study also examined the effects of combining bendamustine with ATM/ATR inhibitors (KU-60019 and VE-821) on lymphoma cells. KU-60019 and/or VE-821 enhanced the activity of bendamustine across all tested cell lines but did not influence MK615’s effects. This suggests that these inhibitors and MK615 likely share a similar mechanism of action. The findings indicate that combining ATM/ATR inhibitors with bendamustine could be a promising approach for treating malignant KU-60019 lymphoma.