N-acetylcysteine and Vitamin C stimulate MYC binding to EGR1 and selectively stimulate apoptosis in B cell lymphoma

Refractory and relapsed B cell lymphomas are often driven by MYC, a difficult-to-target oncogene due to its central role in normal transcription. Here we report that N-acetylcysteine (NAC) and vitamin C (VitC)—in doses that reduce reactive oxygen species levels levels—trigger apoptosis in human B lymphoma cells with high MYC expression. Intraperitoneal NAC and VitC injections dose-dependently reduced tumor growth in xenograft experiments, and combined NAC/VitC administration stopped tumor growth. Knockdown of MYC restored tumor growth in the presence of NAC and VitC and switching-on MYC expression in B cells rendered them sensitive to the compounds. The compounds stimulated MYC binding to Early growth response protein 1 (EGR1)—an interaction found to require Cys132 of MYC—which reduced MYC binding to promotors of cell cycle genes and increased binding to apoptotic genes; and thus, switched MYC’s transcriptional output from cell cycle to apoptosis gene expression. Short-term combined NAC/VitC administration into λMYC transgenic mice, an endogenous mouse model of B cell lymphoma, after tumor onset increased survival fourfold; and life-long oral administration of NAC and VitC stimulated apoptosis and reduced B cell progenitors in the spleen and measurably increased survival. The results provide a rationale with mechanistic understanding for evaluating the therapeutic efficacy of NAC and VitC in patients with MYC-driven B cell lymphoma. 2 cell lines, 3 treatments