Background:The potentiation of Bcl-2 inhibitors (ABT263 and ABT199) and an antidiabetic drug metformin by cotreatment with recombinant human arginase (rhArg) was investigated in a panel of human cancer cell lines modeling pancreatic ductal carcinoma (PDAC), triple-negative breast cancer (TNBC), colorectal cancer (CRC) and glioblastoma (GBM).Methods: rhArg was combined with Bcl-2 inhibitors and metformin.The combination effects were evaluated in vitro.Western blot analysis was used to evaluate the expression of apoptotic and cell cycle markers.MTT assay was used to evaluate the combination efficacy.Flow cytometric assays were used to investigate the apoptotic and cell cycle effects. Results:The combination of rhArg with sublethal doses of ABT263 significantly induced apoptosis, with elevated expression of apoptotic markers.The combination inhibited CDK2 and cyclin A expression, indicating that the observed synergy resulted from both cell death and cell cycle arrest.The combination of rhArg with escalating doses of ABT263 also induced a dose-dependent response.We also found that rhArg + metformin was synergistic in a time-dependent manner.Compared to other amino acid depletion agents, rhArg + ABT263 was the most favorable combination pair.Conclusions: ABT263, a clinical trial phase II drug candidate, and rhArg represent a promising broad-spectrum antitumor combination with clinical potential.
Sze et al. (Wed,) studied this question.