Targeting the ARHGAP18/PI3K/AKT axis with vincristine and cytarabine synergistically suppresses senescence and induces apoptosis in AML

Abstract Background: Cytarabine-based regimens remain the backbone of AML induction and consolidation therapy, yet drug resistance and relapse continue to hinder long-term outcomes. Vincristine is rarely used in AML, and its potential synergy with cytarabine has not been fully elucidated. Methods: IC50 values were determined via CCK-8 assay, followed by assessment of apoptosis, cell cycle, and senescence. Drug synergy was evaluated using the combination index. Immunofluorescence was used to examine microtubules and ARHGAP18 expression. In vivo efficacy was assessed using a xenograft AML model with bioluminescence imaging and survival analysis. Flow cytometry quantified leukemic blasts in bone marrow, peripheral blood, and spleen. RNA-seq and Western blotting were conducted to investigate underlying mechanisms. Results: Therapy-induced senescence contributed to cytarabine resistance in AML cells both in vitro and in vivo. Co-treatment with vincristine enhanced cytarabine sensitivity by attenuating cellular senescence. This combination markedly reduced leukemic burden in the bone marrow, peripheral blood, and spleen (Fig. 1A–B), and significantly prolonged the survival of tumor-bearing mice (Fig. 1C). Mechanistically, vincristine decreased the microtubule-associated expression of ARHGAP18, thereby inhibiting the initiation and progression of senescence. Further analysis indicated that ARHGAP18-induced senescence and resistance were mediated via activation of the PI3K/AKT signaling pathway. Conclusion: Vincristine synergizes with cytarabine to overcome therapy-induced senescence in AML by targeting the ARHGAP18/PI3K/AKT axis, offering a promising strategy to enhance therapeutic efficacy. This work was supported by grants from General Projects of Natural Science Foundation of Anhui Province (No.2208085MH217) and Anhui Clinical Medical Research and Translational Project (No.202427b10020036).