A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice

Cortez, Natalia E., Rodriguez Lanzi, Cecilia, Hong, Brian V., Xu, Jihao, Wang, Fangyi, Chen, Shuai, Ramsey, Jon J., Pontifex, Matthew G., 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: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Aug 2022 09:30
Last Modified: 05 Oct 2022 00:09
URI: https://ueaeprints.uea.ac.uk/id/eprint/87237
DOI: 10.1158/2767-9764.CRC-22-0256

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