Work

High-dose vitamin C potently induces apoptosis in acute lymphoblastic leukemia by activating ER stress response

Year: 2025

Type: article

Abstract: Introduction High-dose Vitamin C has shown significant anti-tumor effects in various cancers, including hematological malignancies. However, its therapeutic efficacy against acute lymphoblastic leukemia (ALL) remains underexplored. Methods ALL cell lines and normal bone marrow mononuclear cells were treated with Vitamin C to assess cell viability, apoptosis, proliferation, and cell cycle progression. Colony formation assays evaluated long-term growth. Additionally, transgenic mouse models were employed to evaluate the in vivo antitumor activity of high-dose Vitamin C in ALL. Western blotting, ROS detection 2′,7′-Dichlorofluorescin diacetate (DCFH-DA), and RNA sequencing with GSEA were conducted to explore Vitamin C’s mechanism of action. Results Our results demonstrated that high-dose Vitamin C exhibited potent cytotoxicity toward ALL cells at relatively low concentrations (200 μM) while sparing normal human bone marrow mononuclear cells even at concentrations as high as 1 mM. Vitamin C effectively inhibited ALL cell line proliferation, induced apoptosis, and disrupted cell cycle progression. We further identified that the increased expression of Solute Carrier Family 23 Member 1 (SLC23A1) in ALL cells enhanced their sensitivity to Vitamin C. In SLC23A1 knockout cells, treatment with 200 μM Vitamin C significantly restored cell viability and reduced apoptosis compared to controls. Mechanistically, high-dose Vitamin C induced apoptosis in ALL cells by activating the ER stress response through the PERK/CHOP pathway. Conclusion Taken together, our findings suggest that high-dose Vitamin C demonstrated significant anti-leukemic effects in ALL, showing cytotoxicity at 200 μM. Furthermore, SLC23A1 may serve as a potential biomarker for predicting the therapeutic response to Vitamin C treatment in ALL patients.

Source: Human & Experimental Toxicology

DOI: 10.1177/09603271251345656