Phenazine 5,10-dioxide analogues as potential therapeutics in AML: Efficacy on patient-derived blasts, in zebrafish larvae xenografts and synergy with venetoclax

Although several new therapies against acute myeloid leukaemia (AML) have emerged the past years, patients who are ineligible for intensive chemotherapy are still treated with less effective treatments to minimise therapy-associated mortality. Several phenazine 5,10-dioxide derivates have previously demonstrated to selectively induce apoptosis in human AML cells. In the present work, we have continued investigations on phenazine 5,10-dioxides to reveal their therapeutic potential in AML using in vitro and in vivo experiments. From a panel of primary AML blasts from 61 non-selected patients, 58 showed high or intermediate response to treatment with the phenazine 5,10-dioxides. This included blasts with biological characteristics associated with poor prognosis, such as FLT3 internal tandem duplication, NPM-1 wild type, CD34⁺, and adverse cytogenetics. The phenazine 5,10-dioxides cytotoxicity towards primary blasts correlated with the blast's sensitivity to daunorubicin, presumably due to similar mode of action towards AML cells. Three phenazine 5,10-dioxides had low toxicity in zebrafish larvae, and from these, two were found effective towards zebrafish larvae AML xenografts. Additionally, synergism with the AML drug venetoclax (VTX) was found in the AML cell lines MOLM-13 and MV4-11. The efficacy of phenazine 5,10-dioxides towards primary AML blasts, synergism with VTX and low toxicity in effective concentrations in zebrafish larva AML xenografts suggests potential for these compounds in future AML therapy for patients unfit for intensive chemotherapy.