CHEMOSENSITIZING EFFECT OF APIGENIN ON T-ALL CELL THERAPY

Nigar Huseynova^1*Melisa Çetinkaya²Züleyha Baran³Rovshan I Khalilov¹Afat O Mammadova¹Yusuf Baran^2*

• ¹Baku State University, Baku, Azerbaijan
• ²Izmir Institute of Technology, Urla, İzmir, Türkiye
• ³Anadolu University, Eskişehir, Eskişehir, Türkiye

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with limited therapeutic options and frequent treatment-associated toxicities. L-asparaginase, a cornerstone in T-ALL therapy, is often compromised by hypersensitivity reactions and systemic side effects, emphasizing the need for safer strategies to enhance its efficacy. This study explores the potential of apigenin—a naturally occurring flavonoid with known antioxidant and pro-apoptotic properties—to act as a chemosensitizer for L-asparaginase in MOLT-4 T-ALL cells. Cytotoxicity, assessed via MTT assay, revealed a time-and dose-dependent response for both agents, with a notable reduction in IC₅₀ values when combined. Apoptotic analysis using Annexin V/PI staining showed significantly increased apoptosis in the combination-treated groups compared to individual treatments. Cell cycle analysis indicated that apigenin induced S-phase arrest, while L-asparaginase promoted G1-phase arrest; combined treatment disrupted cell cycle progression at multiple checkpoints. Additionally, JC-1 dye-based flow cytometry demonstrated enhanced mitochondrial membrane depolarization with combination therapy, with up to a 29.2-fold increase in the cytoplasmic-to-mitochondrial fluorescence ratio compared to L-asparaginase alone. These findings suggest that apigenin potentiates L-asparaginase-induced cytotoxicity through mitochondrial dysfunction and intrinsic apoptotic signaling. The combined use of apigenin and L-asparaginase may offer a novel strategy to improve therapeutic outcomes in T-ALL while potentially reducing the toxicity associated with high-dose L-asparaginase monotherapy.