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Targeted Sensitization of Leukemic T-cells to Anticancer Drugs by SIRT1 Agonist SRT-1720
Donika Ivanova1, Dessislava Lazarova2, Zhivko Zhelev3,4
1Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria.
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.
Insights
SRT-1720 enhances chemotherapy by inducing oxidative stress in leukemia cells while protecting normal cells. This strategy shows potential for reducing toxicity in T-cell acute lymphoblastic leukemia (T-ALL) treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Silent Information Regulator 1 (SIRT1) plays a dual role in cancer, acting as a tumor suppressor or promoter.
- Small-molecule SIRT1 activators like SRT-1720 have shown anticancer potential, but their mechanisms in leukemia are unclear.
Purpose of the Study:
- To investigate the effects of SRT-1720 on leukemic and normal lymphocyte redox state and viability.
- To determine if SRT-1720 sensitizes leukemic cells to conventional anticancer drugs.
Main Methods:
- Assessed synergistic, additive, or antagonistic effects of SRT-1720 with anticancer drugs.
- Measured cell viability, proliferation, apoptosis, reactive oxygen species (ROS), and protein carbonyl products.
Main Results:
- SRT-1720 synergized with multiple chemotherapy agents (e.g., barasertib, bortezomib, cisplatin) against leukemic lymphocytes.
- SRT-1720 increased normal lymphocyte tolerance to certain drugs and reduced doxorubicin-induced oxidative stress.
- Synergistic cytotoxicity in leukemic cells involved ROS overproduction and apoptosis induction, distinct from effects on normal cells.
Conclusions:
- SRT-1720 induces oxidative stress and apoptosis in leukemic cells via SIRT1-independent pathways.
- SRT-1720 enhances antioxidant defense in normal lymphocytes through a SIRT1-dependent pathway.
- SRT-1720 shows promise as an adjuvant therapy for T-ALL, potentially allowing for reduced chemotherapy doses and toxicity.
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