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

• Published in: International journal of molecular sciences 2023-06, Vol.24 (13), p.10753
• Main Authors: Cortez, Natalia E, Pathak, Suraj, Rodriguez Lanzi, Cecilia, Hong, Brian V, Crone, Ryman, Sule, Rasheed, Wang, Fangyi, Chen, Shuai, Gomes, Aldrin V, Baar, Keith, Mackenzie, Gerardo G
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Analysis; Animals; Autophagy; Body composition; Cachexia; Cachexia - drug therapy; Cachexia - etiology; Cancer therapies; cancer-associated cachexia; Carcinoma, Pancreatic Ductal - pathology; Chemotherapy; Critical components; Diet; Diet, Ketogenic; Female; Females; Gemcitabine; Health aspects; High fat diet; Intervention; Ketogenesis; ketogenic diet; Low carbohydrate diet; Male; Males; Medical prognosis; Metabolism; Metabolites; Mice; Mortality; Muscle strength; Muscles; Musculoskeletal system; Pancreatic cancer; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Phosphorylation; Skeletal muscle; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310753

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 declined 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 suggest 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.