Anti-leukemic effects investigation of alpha-mangostin: apoptotic induction and synergistic potential with chemotherapeutic drugs, molecular targets in leukemic cell lines and bone marrow-derived acute leukemic cells

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) remain challenging to treat because of treatment-related toxicity, drug resistance, and disease relapse. Alpha-mangostin, a xanthone derivative from Garcinia mangostana , has demonstrated anticancer and pro-apoptotic activities in several experimental models. This study investigated the cytotoxic and apoptosis-associated effects of alpha-mangostin in acute leukemic cells and its interaction with daunorubicin. Cytotoxicity was assessed by MTT assay in NB-4 and MOLT-4 cell lines and normal peripheral blood mononuclear cells. Drug interactions with daunorubicin were evaluated using the Chou-Talalay combination index method. Apoptosis was assessed by Annexin V/PI flow cytometry in leukemic cell lines and patient-derived bone marrow leukemic cells. Predicted protein associations were explored using STITCH. Expression of PARP1 , caspase-3 , caspase-8 , and caspase-9 was evaluated by RT-qPCR, and PARP1 and caspase-3 cleavage by western blotting. Statistical analyses were performed using unpaired two-tailed Student’s t-tests or one-way ANOVA followed by Sidak’s multiple-comparisons test. Alpha-mangostin showed dose- and time-dependent cytotoxicity, with IC 50 values of 37.21 and 35.61 µM at 24 h and 18.76 and 19.67 µM at 48 h in NB-4 and MOLT-4 cells, respectively. At 48 h, selectivity indices were 1.77 and 1.69, respectively. At the IC 50 combination, combination index values were 0.89–0.92 in NB-4 and 0.81 in MOLT-4, whereas values at the half-IC 50 combination were > 1. Alpha-mangostin increased total apoptosis to 43.17 ± 2.45% in NB-4 and 40.00 ± 5.79% in MOLT-4 cells. In patient-derived cells, total apoptosis was 22.58 ± 2.80% in AML and 21.46 ± 3.29% in ALL samples. Alpha-mangostin treatment was also associated with increased expression of apoptosis-related genes and increased cleavage of PARP1 and caspase-3. Alpha-mangostin exhibited cytotoxic and pro-apoptotic activity in acute leukemic cell lines and patient-derived leukemic cells. Its interaction with daunorubicin was concentration-dependent, with combination index values below 1 at the IC 50 combination but not at the half-IC 50 combination. The modest selectivity indicates a limited in vitro therapeutic window. Further mechanistic and in vivo studies are warranted to determine its therapeutic relevance in acute leukemia.