Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta.
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.
Chinery
R
R
Department of Cell Biology, Vanderbilt University Medical Center, and Veterans Affairs Medical Center, Nashville, Tennessee 37232, USA.
Brockman
J A
JA
Peeler
M O
MO
Shyr
Y
Y
Beauchamp
R D
RD
Coffey
R J
RJ
D000111:Acetylcysteine / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000627:therapeutic use; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011759:Pyrrolidines / Q000627:therapeutic use; D013859:Thiocarbamates / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014810:Vitamin E / Q000627:therapeutic use
D000970:Antineoplastic Agents; D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011759:Pyrrolidines; D013859:Thiocarbamates; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014810:Vitamin E; C020972:pyrrolidine dithiocarbamic acid; D004317:Doxorubicin; D005472:Fluorouracil; D000111:Acetylcysteine