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Research Article

p28-mediated Activation of p53 in G2/M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy

Tohru Yamada, Tapas K. Das Gupta and Craig W. Beattie
Tohru Yamada
Surgery, Division of Surgical Oncology, University of Illinois College of Medicine
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  • For correspondence: tohru@uic.edu
Tapas K. Das Gupta
Surgery, Division of Surgical Oncology, University of Illinois
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Craig W. Beattie
Surgical Oncology, University of Illinois, Chicago
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DOI: 10.1158/0008-5472.CAN-15-2355
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Abstract

p28 is an anionic cell-penetrating peptide of 28 amino acids that activates wild type and mutated p53, leading subsequently to selective inhibition of CDK2 and cyclin A expression and G2/M cell cycle arrest. In this study, we investigated the cytotoxic effects of p28 treatment alone and in combination with DNA damaging and anti-mitotic agents on human cancer cells. p28 enhanced the cytotoxic activity of lower concentrations (IC20-50) of DNA damaging drugs (doxorubicin, dacarbazine, temozolamide) or anti-mitotic drugs (paclitaxel, docetaxel) in a variety of cancer cells expressing wild type or mutated p53. Mechanistic investigations revealed that p28 induced a post-translational increase in the expression of wild type or mutant p53 and p21, resulting in cell cycle inhibition at G2/M phase. Thus, the enhanced activity of these anticancer agents in combination with p28 was facilitated through the p53/p21/CDK2 pathway. Taken together, these results highlight a new approach to maximize the efficacy of chemotherapeutic agents while reducing dose-related toxicity.

  • Received August 28, 2015.
  • Revision received January 11, 2016.
  • Accepted January 15, 2016.
  • ©2015 American Association for Cancer Research.
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Published OnlineFirst February 26, 2016
doi: 10.1158/0008-5472.CAN-15-2355

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p28-mediated Activation of p53 in G2/M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy
Tohru Yamada, Tapas K. Das Gupta and Craig W. Beattie
Cancer Res February 26 2016 DOI: 10.1158/0008-5472.CAN-15-2355

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p28-mediated Activation of p53 in G2/M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy
Tohru Yamada, Tapas K. Das Gupta and Craig W. Beattie
Cancer Res February 26 2016 DOI: 10.1158/0008-5472.CAN-15-2355
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

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