Synergistic antileukemic effects of hydroxyurea and SRJ23 in T-cell acute lymphoblastic leukemia

Background T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive blood cancer associated with high relapse rates, affecting about 15% of pediatric and 25% of ALL cases. Initial management typically involves hydroxyurea (HU) to reduce elevated white blood cell counts before intensive chemotherapy. However, despite this approach, recurrence remains a substantial challenge, even with stem cell transplants. A promising therapeutic strategy for T-ALL might involve combining HU with an additional compound that can enhance cancer cell inhibition. SRJ23, a semi-synthetic andrographolide derivative, is a potential candidate due to its unique mechanism of inhibiting the GDP-GTP exchange, targeting the oncogenic K-Ras mutation pathway implicated in T-ALL progression. This study investigates the potential of HU and SRJ23 as a combined treatment to enhance apoptotic induction in T-ALL cells. Methods JCLs is an immortalized lines of human T lymphocyte cells that are used to study T-ALL. They were cultured and treated with varying concentrations of HU (7.8–1000 µM) and SRJ23 (0.1–100 µM), individually and in combination, for 96 h. The cell viability was then assessed using the MTT assay. The drug interactions were calculated using the CompuSyn software, which runs the Chou-Talalay method to calculate the combination index (CI) and generate isobolograms, allowing for the quantitative, determination of synergistic, additive, or antagonistic effects between the two compounds. We used the FITC Annexin V/PI Apoptosis Detection Kit to analyse the treated cells with BD FACS LSRFortressa™ Cell Analyser and FACSDiva™ Software to quantify early and late apoptotic populations. Results Our study shows a significant decline in the JCLs viability resulting from the exposure of HU and SRJ23, especially when in both drugs were in combination. A synergistic effect was observed at two occasions that is when 10 µM SRJ23 combined with 125 µM HU and 10 µM SRJ23 combined with 250 µM of HU on the dose–response curves. These combination treatment induced apoptosis confirmed by Annexin V-FITC staining. Conclusion To our knowledge, our study is the first to prove that the combination of HU and SRJ23 exerts a synergistic effect against JCLs and has a significant inhibitory effect in vitro with a remarkable ability to induce apoptosis. Further in-vitro and animal research is deemed required to thoroughly understand the detailed impact of this novel HU and SRJ23 synergism before it can be embarked as a potential novel targeted T-ALL chemotherapy.

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