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Cortez, Natalia E., Rodriguez Lanzi, Cecilia, Hong, Brian V., Xu, Jihao, Wang, Fangyi, Chen, Shuai, Ramsey, Jon J., Pontifex, Matthew G. 
ORCID: https://orcid.org/0000-0003-2174-2313, Müller, Michael ORCID: https://orcid.org/0000-0002-5930-9905, Vauzour, David ORCID: https://orcid.org/0000-0001-5952-8756, Vahmani, Payam, Hwang, Chang-Il, Matsukuma, Karen and Mackenzie, Gerardo G.
(2022)
A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.
Cancer Research Communications, 2 (9).
951–965.
ISSN 2767-9764
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.
| Item Type: | Article |
|---|---|
| Additional Information: | Acknowledgments: This research was funded by the University of California, Davis, the UCD Comprehensive Cancer center (ELEMENTS initiative), and NIFA-USDA (CA-D-NTR-2397-H) to G.G. Mackenzie, as well as UC Davis Academic Senate to C.-il Hwang and G.G. Mackenzie. N.E. Cortez is a fellow of CONACYT-UCMEXUS. This research was also supported by the Biorepository and Biostatistics Shared Resources, funded by the UC Davis Comprehensive Cancer Center Support Grant awarded by the NCI (P30CA093373). Note: Supplementary data for this article are available at Cancer Research Communications Online (https://aacrjournals.org/cancerrescommun/). |
| Uncontrolled Keywords: | oncology,cancer research,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2730 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 15 Aug 2022 09:30 |
| Last Modified: | 17 Jun 2024 08:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/87237 |
| DOI: | 10.1158/2767-9764.CRC-22-0256 |
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