The full potential of chemotherapy can be limited in practice by toxic side effects. Therefore, strategies or interventions that are effective in selectively protecfing normal cells, but not cancer cells, are predicted to increase the therapeutic window and clinical effectiveness of chemotherapy. Published literature demonstrates that mice subjected to short-term stan/ation are protected from high doses of etoposide that kill their fed littermates. In addition, tumor cells carrying mutations that cause constitutive activation of the PI3K pathway have been shown to be insensitive to the anti-growth effects of dietary restriction when grown as xenografts in mice. Thus, fasting may enhance the effectiveness of chemotherapy by protecting normal cells, but not cancer cells, frcim the toxic effects of chemotherapy and clinical trials are currently being conducted to test whether fasting prior to or during chemotherapy reduces associated side-effects in cancer patients. However, little is known about the molecular mechanisms mediating the differential response of normal cells compared with cancer cells to short-term starvation. Using a reporter mouse engineered to express firefly luciferase from the endogenous p21 promoter, we observe a potent induction of p21 expression in response to short-term stan/ation. Interestingly, this occurs in metabolic organs and p21 expression was also observed, forthe first time, in particular neurons ofthe hypothalamus that regulate metabolism. Our preliminary studies also demonstrate that p21 protects cells from the DNA damaging effects of irinotecan, a topoisomerase 1 inhibitor used clinically to treat certain types of cancer. Thus, experiments proposed in this applicafion will (1) determine if induction of p21 expression by short-term starvation protects mice from the lethal effects of high dose chemotherapy and ionizing radiation, (2) identify the signaling pathway(s) responsible for activating p21 expression in response to short-term starvation and (3) determine if short-term stan/ation protects mice, but not PTEN-deficient prostate cancers growing in these mice, from chemotherapy and radiation therapy.

Public Health Relevance

Results from our studies could dramafically change our approach to chemotherapy with a readily translatable inten/ention, pre-therapy fasting. In addition, by delineating the signaling pathway(s) that are activated by short-term starvation and that protect normal cells from the toxic effects of genotoxic stress, our studies may identify novel targets for the development of agents that serve as chemoprotectants and/or radioprotectants for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA094056-12
Application #
8195496
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-08-27
Budget End
2012-12-31
Support Year
12
Fiscal Year
2012
Total Cost
$116,471
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Meinerz, Kelsey; Beeman, Scott C; Duan, Chong et al. (2018) Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo, and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin). Appl Magn Reson 49:3-24
Zheleznyak, Alexander; Shokeen, Monica; Achilefu, Samuel (2018) Nanotherapeutics for multiple myeloma. Wiley Interdiscip Rev Nanomed Nanobiotechnol 10:e1526
Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494
Kotagiri, Nalinikanth; Cooper, Matthew L; Rettig, Michael et al. (2018) Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer. Nat Commun 9:275
Murali, Bhavna; Ren, Qihao; Luo, Xianmin et al. (2018) Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss. Cancer Res 78:5618-5630
Miller, Jessica; Wang, Steven T; Orukari, Inema et al. (2018) Perfusion-based fluorescence imaging method delineates diverse organs and identifies multifocal tumors using generic near-infrared molecular probes. J Biophotonics 11:e201700232
Zacharias, Niki; Lee, Jaehyuk; Ramachandran, Sumankalai et al. (2018) Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo. Mol Imaging Biol :
Cherian, Mathew A; Olson, Sydney; Sundaramoorthi, Hemalatha et al. (2018) An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. J Biol Chem 293:6844-6858
Hövener, Jan-Bernd; Pravdivtsev, Andrey N; Kidd, Bryce et al. (2018) Parahydrogen-Based Hyperpolarization for Biomedicine. Angew Chem Int Ed Engl 57:11140-11162
Bauerle, Kevin T; Hutson, Irina; Scheller, Erica L et al. (2018) Glucocorticoid Receptor Signaling Is Not Required for In Vivo Adipogenesis. Endocrinology 159:2050-2061

Showing the most recent 10 out of 283 publications