Combinational Therapy of Acute Lymphoblastic Leukemia with Cyclophosphamide and BV6 Synergistically Induces Apoptosis in Leukemic Cells

Background: Acute lymphoblastic leukemia (ALL), a hematological malignancy, is associated with the accumulation of lymphoblasts in hematopoietic tissues and the peripheral blood (PB). A major obstacle in ALL treatment is the failure to undergo apoptosis, thus resulting in relapses. Cyclophosphamide is an alkylating agent widely used to treat various cancers. BV6 is another agent, under preclinical and clinical trials, which inhibits the function of inhibitors of apoptosis proteins (IAPs) in cells. According to previous studies, IAPs are highly overexpressed in ALL cells. Also, the intrinsic apoptosis pathway is reported to be dysfunctional in ALL cells, making BV6 a new promising option due to its potential to induce extrinsic cell death as well. Methods: In the current study, the inhibitory effect of the combinational treatment of cyclophosphamide and BV6 was studied on the cell growth of eleven ALL patients using an MTT test. Subsequently, the effect of the treatment was studied on TNF-α secretion as well. Finally, we measured the DNA fragmentation rates of treated cells as well. Results: The results indicated a synergistic effect between the drugs on the viability of cells. Also, the impact of the cotreatment was increased in a time-dependent manner. We also found that BV6, but not cyclophosphamide, induces TNF-α secretion, activating the extrinsic apoptosis pathway as well. Conclusion: BV6, by inducing intrinsic and extrinsic pathways, overcomes cyclophosphamide resistance. These results suggest the combinational use of BV6 and cyclophosphamide for the treatment of ALL patients. Inhibition of IAPs helps overcome the failure to undergo apoptosis and can improve the prognosis of ALL patients.