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

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      Publication date:
      Journal: Nature medicine
      Keywords: Acetylcysteine, therapeutic use, Antineoplastic Agents, Antioxidants, Apoptosis, drug effects, CCAAT-Enhancer-Binding Proteins, Colorectal Neoplasms, drug therapy, metabolism, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, biosynthesis, DNA-Binding Proteins, Doxorubicin, Drug Interactions, Enzyme Inhibitors, Fluorouracil, Humans, Nuclear Proteins, Pyrrolidines, Thiocarbamates, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, physiology, Vitamin E

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          Abstract

          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.

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          Most cited references36

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          p53 mutations in human cancers

          M Hollstein, D Sidransky, B Vogelstein … (1991)
          Article 0 comments Cited 488 times – based on 0 reviews     Review now
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            An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.

            A Beg, D Baltimore (1996)
            Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA-/- fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-alpha. These results have implications for the treatment of inflammatory and proliferative diseases.
            Article 0 comments Cited 381 times – based on 0 reviews     Review now
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              Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.

              Chuxia Deng, Pumin Zhang, J. Wade Harper … (1995)
              p21CIP1/WAF1 is a CDK inhibitor regulated by the tumor suppressor p53 and is hypothesized to mediate G1 arrest. p53 has been suggested to derive anti-oncogenic properties from this relationship. To test these notions, we created mice lacking p21CIP1/WAF1. They develop normally and (unlike p53-/- mice) have not developed spontaneous malignancies during 7 months of observation. Nonetheless, p21-/- embryonic fibroblasts are significantly deficient in their ability to arrest in G1 in response to DNA damage and nucleotide pool perturbation. p21-/- cells also exhibit a significant growth alteration in vitro, achieving a saturation density as high as that observed in p53-/- cells. In contrast, other aspects of p53 function, such as thymocytic apoptosis and the mitotic spindle checkpoint, appear normal. These results establish the role of p21CIP1/WAF1 in the G1 checkpoint, but suggest that the anti-apoptotic and the anti-oncogenic effects of p53 are more complex.
              Article 0 comments Cited 295 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 9359698
                DOI:: 10.1038/nm1197-1233

                ScienceOpen disciplines: Chemistry
                Keywords: Acetylcysteine,therapeutic use,Antineoplastic Agents,Antioxidants,Apoptosis,drug effects,CCAAT-Enhancer-Binding Proteins,Colorectal Neoplasms,drug therapy,metabolism,Cyclin-Dependent Kinase Inhibitor p21,Cyclins,biosynthesis,DNA-Binding Proteins,Doxorubicin,Drug Interactions,Enzyme Inhibitors,Fluorouracil,Humans,Nuclear Proteins,Pyrrolidines,Thiocarbamates,Transcription Factors,Tumor Cells, Cultured,Tumor Suppressor Protein p53,physiology,Vitamin E
                Data availability:
                ScienceOpen disciplines: Chemistry
                Keywords: Acetylcysteine, therapeutic use, Antineoplastic Agents, Antioxidants, Apoptosis, drug effects, CCAAT-Enhancer-Binding Proteins, Colorectal Neoplasms, drug therapy, metabolism, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, biosynthesis, DNA-Binding Proteins, Doxorubicin, Drug Interactions, Enzyme Inhibitors, Fluorouracil, Humans, Nuclear Proteins, Pyrrolidines, Thiocarbamates, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, physiology, Vitamin E

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