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Nitric Oxide Donors Are a New Class of Anti-cancer Therapeutics for the Reversal of Resistance and Inhibition of Metastasis

  • Benjamin Bonavida
  • Stavroula Baritaki
  • Sara Huerta-Yepez
  • Mario I. Vega
  • Ali R. Jazirehi
  • James Berenson
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Several novel therapeutic strategies are currently being explored for the treatment of tumors that are refractory to conventional cytotoxic therapies. Further, therapies aimed at the prevention and treatment of metastasis are also being investigated in pre-clinical and clinical studies. Most of these novel therapeutics are aimed at targeting gene products that regulate resistance and metastasis and have yielded several FDA-approved drugs/antibodies for the treatment of specific cancers. Nitric oxide donors, such as nitroglycerine which has been approved for the treatment of cardiovascular diseases, have been examined for their potential role in the treatment of cancer. NO donor-induced anti-tumor activities have been documented in several in vitro and in vivo animal studies. In addition, nitroglycerine therapeutic application in cancer patients has been initiated. Depending on the level of NO released and sustained, it is well documented that high levels of NO are anti-tumorigenic due to their complex activities, such as inhibiting constitutively hyperactivated cell survival/anti-apoptotic pathways and leading to their ability to sensitize drug/immune-resistant tumor cells to apoptosis by cytotoxic drugs. In addition, inhibition of such survival pathways also leads to the regulation of gene products that participate in the epithelial to mesenchymal transition (EMT) and metastasis and result in the inhibition of metastasis. Hence, NO donors can exert simultaneously a multitude of anti-cancer activities, including enhancement of apoptotic stimuli, inhibition of metastasis, inhibition of angiogenesis, and inhibition of hypoxia, depending on the concentration of the NO donor and on the cancer type and stage. Therefore, while novel therapeutics are being tested for specific anti-tumor targeting effects, we suggest that activation of endogenous iNOS or exogenous NO donors can substitute a large number of specific agents and may be considered as universal anti-cancer therapeutics when used alone or in combination with subtoxic cytotoxic drugs. Thus, the development of a new generation of NO donors with minimal toxicity and higher anti-tumor efficacy is warranted for investigation in clinical trials in cancer patients

Keywords

Nitric Oxide Nitric Oxide Synthases Chemotherapeutic Drug Sensitize Tumor Cell Tumor Cell Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author acknowledges the various associates in his laboratory and collaborators for their valuable contributions and whose works were an integral part of this manuscript. The author is also grateful for the assistance of Katherine Wu, Erica Keng, and Tiffany Chin in the preparation of this manuscript. The continuous assistance of the UCLA Jonsson Comprehensive Cancer Center is also acknowledged.

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© Springer Science + Business Media, LLC 2010

Authors and Affiliations

  • Benjamin Bonavida
    • 1
  • Stavroula Baritaki
    • 1
  • Sara Huerta-Yepez
    • 2
  • Mario I. Vega
    • 3
  • Ali R. Jazirehi
    • 1
  • James Berenson
    • 4
  1. 1.Department of Microbiology, Immunology and Molecular GeneticsJonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los AngelesLos AngelesUSA
  2. 2.Unidad de Invastigacion en Enfarmeda des OncologicasHospital Infantil de Mexico, Federico GomezMexico CityMexico
  3. 3.Unidad de Investigacion Medica En Inmunologia e InfactologiaHospital de Infectologia. CMN “LA Caza” IMSSMexico CityMexico
  4. 4.Hematology/OncologyInstitute for Myeloma & Bone Cancer ResearchWest HollywoodUSA

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