L-Ascorbic Acid and α-Tocopherol Synergistically Triggers Apoptosis Inducing Antileukemic Effects of Arsenic Trioxide via Oxidative Stress in Human Acute Promyelocytic Leukemia Cells

Chemosensitization is an effective strategy to overcome the drawbacks of arsenic trioxide (As(2)O(3)) treatment, which may be possible through the use of dietary supplements in combination. The present investigation evaluates the synergistic mechanism of action of vitamins, such as L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) in As(2)O(3) chemotherapy using human leukemia (HL-60) cells. In vitro assays on the cytotoxicity of As(2)O(3) and vitamins and cellular apoptotic evidences were done; a proteomic investigation with mass spectrometry was also performed. The combination of L-AA and α-TOC potentiates As(2)O(3) cytotoxicity in HL-60 cells, substantiated by depletion in antioxidant status, mitochondrial transmembrane potential, and inhibition of nuclear factor erythroid 2-related factor 2 and B-cell lymphoma 2 transcription factors. Mass spectrometry results showed decreased expression of proteins regulating cell cycle and translation in cells treated with As(2)O(3), L-AA, and α-TOC when compared with As(2)O(3)-treated sample. In addition, this combination treatment identified numerous proteins associated with apoptosis and cell stress. HL-60 cells became more prone to As(2)O(3) on exposure to L-AA and α-TOC, indicating that this combination may be a promising approach to increase the outcome of As(2)O(3) chemotherapy.