Abstract
Cancer therapy has witnessed major advances in the last few decades. However, the conventional therapies have a narrow therapeutic application, and the responses produced are generally unpredictable and are often non-curative. New strategies to combat cancer are being developed, one of the most promising of which is the use of non-genotoxic chemicals that are able to rescue the tumor suppressor function of p53 in cancer cells. In this review, we first discuss: (i) the current knowledge on the role of p53 in determining the fate of human normal and malignant cells following exposure to cancer therapeutic agents; and (ii) the biological consequences of the failure of cancer cells to implement p53-mediated responses in terms of development of highly metastatic “karyoplasts” which exhibit both selfrenewal and treatment-resistant properties. We next provide an update on the potential anticancer properties of diverse types of pharmacological modulators of p53, including histone deacetylase inhibitors (e.g., trichostatin A), aromatase inhibitors (e.g., Anastrozole), and the nuclear export inhibitor leptomycin B. In addition, we highlight the various shortcomings of in vitro assays that are universally used for preclinical evaluation of anti-neoplastic properties of new drugs, and describe alternative cytotoxicity assays that circumvent some of these shortcomings.
Keywords: p53 signaling, pharmacological modulators of p53, cancer therapy, cytotoxicity assays, apoptosis, accelerated senescence
Current Signal Transduction Therapy
Title: Pharmacological Modulation of p53 Function in Cancer Therapy
Volume: 3 Issue: 3
Author(s): Razmik Mirzayans and David Murray
Affiliation:
Keywords: p53 signaling, pharmacological modulators of p53, cancer therapy, cytotoxicity assays, apoptosis, accelerated senescence
Abstract: Cancer therapy has witnessed major advances in the last few decades. However, the conventional therapies have a narrow therapeutic application, and the responses produced are generally unpredictable and are often non-curative. New strategies to combat cancer are being developed, one of the most promising of which is the use of non-genotoxic chemicals that are able to rescue the tumor suppressor function of p53 in cancer cells. In this review, we first discuss: (i) the current knowledge on the role of p53 in determining the fate of human normal and malignant cells following exposure to cancer therapeutic agents; and (ii) the biological consequences of the failure of cancer cells to implement p53-mediated responses in terms of development of highly metastatic “karyoplasts” which exhibit both selfrenewal and treatment-resistant properties. We next provide an update on the potential anticancer properties of diverse types of pharmacological modulators of p53, including histone deacetylase inhibitors (e.g., trichostatin A), aromatase inhibitors (e.g., Anastrozole), and the nuclear export inhibitor leptomycin B. In addition, we highlight the various shortcomings of in vitro assays that are universally used for preclinical evaluation of anti-neoplastic properties of new drugs, and describe alternative cytotoxicity assays that circumvent some of these shortcomings.
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Cite this article as:
Mirzayans Razmik and Murray David, Pharmacological Modulation of p53 Function in Cancer Therapy, Current Signal Transduction Therapy 2008; 3 (3) . https://dx.doi.org/10.2174/157436208785699721
DOI https://dx.doi.org/10.2174/157436208785699721 |
Print ISSN 1574-3624 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-389X |
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