Dual Targeting of ALDH1 and ALDH3: A Promising Therapeutic Approach in Acute Myeloid Leukemia

Background. The aldehyde dehydrogenasesfamily(ALDHs) play a major cytoprotective role in cells via detoxification of a wide range of aldehydes. Their functional activity also extends to modulation of cell proliferation, differentiation and survival of cancer cells. Nevertheless, the identity of the specific isoforms contributing to this in acute myeloid leukemia (AML), the underlying mechanisms and the therapeutic value of ALDH inhibitors remain elusive.

Methods. We conducted a meta-analysis to investigate the impact of ALDHs on clinicopathological parameters and survival in AML patients. The expression of ALDHs and their corresponding enzymatic activities were monitored in AML patient-derived cells (n=83) and pharmacologically inhibited with DIMATE, an irreversible suicide inhibitor of ALDH1 and ALDH3. Targeting of ALDH was evaluated both, in vitro and in orthotopic xenograft tumor models and the molecular mechanisms associated were studied in loss-of-function experiments, luciferase reporter assays and combination-index for DIMATE-drug interactions.

Results. We detected gene amplification or mRNA upregulation of ALDH1 and ALDH3 subfamilies in about 45% of AML (n = 200). The expression of these isoenzymes revealed shorter survival times in patients and strong impact on chemotherapy resistance. Lower enzymatic activity of ALDH was noted in AML patients in the favorable cytogenetic risk group. Consistently, the ALDH activity was significantly higher in patients with refractory AML (>5% blasts after first line treatment) compared to non-refractory patients (p<0,005). Simultaneous inhibition of ALDH1 and 3 activates JNK signaling, compromises glutathione homeostasis and induces a redox state imbalance that is amplified by the accumulation of malondialdehyde and 4-hydroxynonenal-protein adducts. This condition ultimately results in severe oxidative damage and cell death. In AML xenografts with high to moderate resistance to cytarabine, combination with DIMATE promoted strong synergistic responses.

Conclusion. These results provide a proof of concept that AML with increased expression of ALDH1 and 3 may benefit from strategies including inhibitors of these isoenzymes, as single agents or in combination with chemotherapy to overcome patient-specific drug resistance. For these patients, who often have poor responses and no alternative therapeutic plan, DIMATE could be a promising option.