Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta.

Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp RD, Coffey RJ
Nat Med. 1997 3 (11): 1233-41

PMID: 9359698 · DOI:10.1038/nm1197-1233

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.

MeSH Terms (21)

Acetylcysteine Antineoplastic Agents Antioxidants Apoptosis CCAAT-Enhancer-Binding Proteins Colorectal Neoplasms Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins Doxorubicin Drug Interactions Enzyme Inhibitors Fluorouracil Humans Nuclear Proteins Pyrrolidines Thiocarbamates Transcription Factors Tumor Cells, Cultured Tumor Suppressor Protein p53 Vitamin E

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