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
Pisaneschi, Federica; Kelderhouse, Lindsay E; Hardy, Amanda et al. (2017) Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers. Bioconjug Chem 28:583-589
Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D et al. (2017) Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 214:2843-2857
Zhang, Daoxiang; Li, Lin; Jiang, Hongmei et al. (2017) Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:1748-1759
Lu, Zhi Hong; Kaliberov, Sergey; Sohn, Rebecca E et al. (2017) A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector. Oncotarget 8:12272-12289
Miller, Jessica; Wang, Steven T; Orukari, Inema et al. (2017) Perfusion-based fluorescence imaging method delineates diverse organs and identifies multifocal tumors using generic near-infrared molecular probes. J Biophotonics :
Miller, Jessica P; Habimana-Griffin, LeMoyne; Edwards, Tracy S et al. (2017) Multimodal fluorescence molecular imaging for in vivo characterization of skin cancer using endogenous and exogenous fluorophores. J Biomed Opt 22:66007
Zacharias, Niki Marie; McCullough, Christopher; Shanmugavelandy, Sriram et al. (2017) Metabolic Differences in Glutamine Utilization Lead to Metabolic Vulnerabilities in Prostate Cancer. Sci Rep 7:16159
Gilson, Rebecca C; Black, Kvar C L; Lane, Daniel D et al. (2017) Hybrid TiO2 -Ruthenium Nano-photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions. Angew Chem Int Ed Engl 56:10717-10720
Tang, Rui; Habimana-Griffin, LeMoyne M; Lane, Daniel D et al. (2017) Nanophotosensitive drugs for light-based cancer therapy: what does the future hold? Nanomedicine (Lond) 12:1101-1105
Miller, Jessica P; Maji, Dolonchampa; Lam, Jesse et al. (2017) Noninvasive depth estimation using tissue optical properties and a dual-wavelength fluorescent molecular probe in vivo. Biomed Opt Express 8:3095-3109

Showing the most recent 10 out of 273 publications