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

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 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.

Hepatic safety profile of pancreatic cancer‑bearing mice fed a ketogenic diet in combination with gemcitabine

“…It was observed that a KD combined with gemcitabine significantly increased liver lysine acetylation in females, but not males, when compared with CG-treated mice. Interestingly, previously published data elucidated sex-dependent effects of KG treatment in the skeletal muscle of KPC animals ( 11 ), so the results of the present study highlight the importance of researching the multi-organ effects of treatments in both males and females. Unfortunately, as the research design of the present study did not include KPC mice fed with a KD alone, the exploration of the exact contribution of the KD to this effect was impeded.…”

“…It has been recently reported that a KD plus gemcitabine enhances overall survival and mitigates cachexia in KPC mice compared with mice fed a CD ( 11 , 12 ). Based on these promising results, the present secondary analysis was performed to evaluate the impact of a KD in combination with gemcitabine on the liver safety profile in KPC mice.…”

“…Therefore, hepatic metabolism serves a major role in substrate availability and metabolic alterations during fasting or with fasting mimicking diets such as KDs, especially when given simultaneously with chemotherapy ( 8 – 10 ). It was recently reported that a KD enhances the anticancer effect of gemcitabine (2′,2′-difluoro-2′-deoxycytidine), improves survival and mitigates cachexia in LSL-Kras LSL-G12D/+ Trp53 R172H/+ Pdx-1 - Cre (KPC) tumor-bearing mice ( 11 , 12 ). Although additional evidence on the efficacy of KDs in combination with chemotherapy exists ( 4 , 13 ), little is known regarding the safety of KDs with or without concomitant treatment with gemcitabine, an antineoplastic drug commonly used in pancreatic cancer treatment.…”

Ketogenic diet and behavior: insights from experimental studies

“…However, despite the equivalent caloric intake, feeding with KD often results in improved body mass (26,83,138,140,144) and metabolic health in long-term treatment (65). In some studies, rodents fed with KD consumed more calories than chow-fed controls, which was probably associated with lower energy assimilation because weight gain was not increased (44, 60, 95,135,[150][151][152][153][154][155][156][157][158]. One exception is a study in the model of Dravet syndrome where increased calorie intake was accompanied by increased body weight probably resulting from improvement of other disease symptoms (44).…”