Nitazoxanide cooperates with cytarabine to inhibit cytarabine-resistant acute myeloid leukemia progression via mitochondrial dysfunction and PLK1 suppression.

Acute myeloid leukemia (AML) remains a therapeutic challenge due to frequent resistance to cytarabine (Ara-C), the standard chemotherapeutic agent. Recent studies implicate mitochondrial oxidative phosphorylation (OXPHOS) as a pivotal driver of this resistance, conferring metabolic adaptability and survival advantages to leukemic cells. In this study, we evaluated the therapeutic potential of repurposing nitazoxanide (NTZ), an FDA-approved antiparasitic drug, to to overcome Ara-C resistance in AML. Our results reveal that NTZ exerts potent cytotoxicity against AML cells and potentiates the cytotoxic impact of Ara-C through a multifaceted mechanism. Specifically, NTZ triggers excessive mitochondrial ROS production, resulting in profound mitochondrial dysfunction. Concurrently, it suppresses Polo-like kinase 1 (PLK1) expression, thereby inducing G2/M cell cycle arrest and activating apoptotic pathways. Collectively, our findings identify NTZ as a potent anti-tumor agent and chemosensitizer that restores Ara-C responsiveness, offering a promising combinatorial strategy for the treatment of refractory AML.