Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Ketogenic Diet in Combination With Gemcitabine Mitigates Pancreatic Cancer Associated Cachexia in Male and Female KPC Mice

Natalia E Cortez
,
Suraj Pathak
,
Cecilia Rodriguez Lanzi
,
Brian Hong
ORCID logo ,
Rasheed O Sule
ORCID logo ,
Ryman Crone
,
Fangyi Wang
,
Shuai Chen
,
Aldrin Gomes
,
Keith Baar
,
Gerardo Guillermo Mackenzie
* ORCID logo
Version 1 : Received: 6 June 2023 / Approved: 7 June 2023 / Online: 7 June 2023 (03:53:16 CEST)

A peer-reviewed article of this Preprint also exists.

Cortez, N.E.; Pathak, S.; Rodriguez Lanzi, C.; Hong, B.V.; Crone, R.; Sule, R.; Wang, F.; Chen, S.; Gomes, A.V.; Baar, K.; Mackenzie, G.G. A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice. Int. J. Mol. Sci. 2023, 24, 10753. Cortez, N.E.; Pathak, S.; Rodriguez Lanzi, C.; Hong, B.V.; Crone, R.; Sule, R.; Wang, F.; Chen, S.; Gomes, A.V.; Baar, K.; Mackenzie, G.G. A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice. Int. J. Mol. Sci. 2023, 24, 10753.

Abstract

Cancer associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG mitigated muscle strength decline over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggests that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

Keywords

cachexia; pancreatic cancer; ketogenic diet; gemcitabine; cancer-associated cachexia

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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