Targeted Sensitization of Leukemic T-cells to Anticancer Drugs by SIRT1 Agonist SRT-1720.

BACKGROUND/AIM: Leukemia therapy targets multiple molecular pathways, including non-oncogenic but clinically relevant factors such as Silent Information Regulator 1 (SIRT1), which acts either as a tumor suppressor or tumor promoter depending on its downstream targets, cancer type, and disease stage. Although small-molecule SIRT1 activators such as SRT-1720 have shown anticancer potential, their molecular mechanisms in leukemia remain insufficiently understood. This study aimed to elucidate the effects of SRT-1720 on the redox state and viability of leukemic lymphocytes and normal lymphocytes, as well as its ability to sensitize leukemic cells to anticancer drugs.

MATERIALS AND

METHODS

The synergistic, additive or antagonistic antiproliferative effects of SRT-1720 and anticancer drugs were examined. The following parameters were analyzed: cell viability and proliferation - by trypan blue staining; apoptosis - by phosphatidylserine expression on the cell surface; and oxidative stress - by detecting intracellular levels of reactive oxygen species (ROS) and protein carbonyl products.

RESULTS

SRT-1720 potentiated the effects of most anticancer drugs in leukemic lymphocytes. Synergism was found in combination with: barasertib, bortezomib, cisplatin, MG-132, bleomycin, ABT-737, lonafarnib, everolimus, and palbociclib. SRT-1720 increased the tolerance of normal lymphocytes to anticancer drugs, as demonstrated for everolimus, barasertib, and doxorubicin. The synergistic cytotoxicity of SRT-1720 in combination with everolimus and barasertib was accompanied by overproduction of ROS and increased induction of apoptosis in leukemic lymphocytes, but not in normal lymphocytes. SRT-1720 favorably affected the viability of normal lymphocytes, reducing oxidative stress and cytotoxicity induced by doxorubicin at the concentrations used in our study.

CONCLUSION

SRT-1720 induces oxidative stress and apoptosis in leukemic lymphocytes through SIRT1-independent pathway(s). In contrast, it enhances antioxidant defense in normal lymphocytes through a SIRT1-dependent pathway. These findings highlight the potential of SRT-1720 as an adjuvant to chemotherapy in T-ALL, particularly in drug combinations demonstrating strong synergism, which may allow dose reduction and decreased toxicity.