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The Role of p53 Synthetic Lethality in Increased Chemosensitivity to DNA-Damaging Agents Conferred by the Exercise Myokine Irisin
Technical Report,15 Sep 2018,14 Sep 2019
University of New Mexico Albuquerque United States
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The goal of this project is to address the overarching challenge to revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. Specifically, we are testing the idea that the exercise myokine Irisin can synergize with DNA damaging chemotherapeutics to induce cytotoxicity with less toxic concentrations of the chemotherapeutic. In year 2 we built upon our in vitro observations from year 1, indicating that irisin may attenuate breast cancer progression by reducing inflammation. Orthotopic xenograft experiments in which MDA-MB-231 tumor-bearing mice were treated with vehicle, doxorubicin Dox, or Dox Low or High Irisin concentrations, demonstrated that tumor growth could be reduced by Dox Low Irisin below that of Dox alone. Moreover, mice treated with Dox Irisin combinations showed less Doxorubicin mediated cytotoxic weight loss compared to Dox alone. Finally, mice treated with Irisin-Dox combination had reduced white adipose tissue depots and lower expression of inflammation markers in both adipose tissue and skeletal muscle. These results suggest that Irisin may attenuate aggressive breast tumor growth when combined with Dox, and concomitantly, irisin may contribute to overall metabolic health by maintaining body weight, possibly through improved muscle mass and reduced white adipose tissue. Attenuation of inflammation may contribute to both positive outcomes.
APPROVED FOR PUBLIC RELEASE