Metformin and chloroquine enhanced the efficacy of cytarabine in acute lymphoblastic leukemia cell lines: a drug repositioning approach.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite advances in the treatment of ALL, high disease recurrence and the impact of chemical toxicity on patients' quality of life persist. Drug repositioning has been proven to have antitumor and anti-inflammatory properties in leukemia. This study investigated the effects of metformin and chloroquine on the efficacy of cytarabine in NALM-6 cells. The growth inhibitory effects of metformin (Met) and chloroquine (CQ) on the response of NALM-6 cells to cytarabine (AraC) were determined via the MTT assay. To test the regeneration potential, a colony formation assay was performed. Apoptosis and cell cycle analyses were executed via flow cytometry. Oxidative stress markers and antioxidant activity were measured. Gene expression analysis and protein measurement of apoptotic and signaling pathways were performed. The administration of metformin and chloroquine increased the efficacy of cytarabine in suppressing NALM-6 cells, leading to decreased colony formation, increased apoptosis, and G1 phase cell cycle arrest. These effects are mediated by the upregulation of TP53, CASP3 and CASP8 genes and the reduction in BCL-2, NRAS and KRAS genes. Our data suggest that the combination of AraC with Met and CQ may be an effective approach for the treatment of B-ALL.