A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

Cortez, Natalia E.; Lanzi, Cecilia Rodríguez; Hong, Brian V.; Xu, Jihao; Wang, Fangyi; Chen, Shuai; Ramsey, Jon J.; Pontifex, Matthew G.; Müller, Michael; Vauzour, David; Vahmani, Payam; Hwang, Chang-il; Matsukuma, Karen; Mackenzie, Gerardo G.

doi:10.1158/2767-9764.crc-22-0256

Cited by 12 publications

(22 citation statements)

References 50 publications

(57 reference statements)

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“…high-fat/protein diet, increases blood levels of the ketone body β-hydroxybutyrate and can improve the efficacy of ICB [21,22]. In one study, KD in combination with gemcitabine has shown to increase by 42% the overall median survival in KPC mice, a model of pancreatic ductal carcinoma.…”

Section: Shaping the Microbiome With The Dietmentioning

confidence: 99%

“…The diet has been shown to be one of the most powerful modulators of microbiota composition. Two recent studies in mice have shown that the ketogenic diet (KD), a low‐carbohydrate, high‐fat/protein diet, increases blood levels of the ketone body β‐hydroxybutyrate and can improve the efficacy of ICB [21, 22]. In one study, KD in combination with gemcitabine has shown to increase by 42% the overall median survival in KPC mice, a model of pancreatic ductal carcinoma.…”

Section: Introductionmentioning

confidence: 99%

“…In one study, KD in combination with gemcitabine has shown to increase by 42% the overall median survival in KPC mice, a model of pancreatic ductal carcinoma. The effect was more pronounced in female mice as compared to males (60% vs. 28% overall median survival) and correlated with several factors, including inhibition of ERK, AKT pathways, and modulation of the gut microbiota [21]. The KD plus gemcitabine reduced the diversity of the microbiota and increased the Firmicutes to Bacteroidetes ratio, with a great increase in Faecalibaculum rodentium .…”

Section: Introductionmentioning

confidence: 99%

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Training the microbiota to increase immune checkpoint blockade and to reduce toxicity

Rescigno

2023

Eur J Immunol

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There is no doubt that immunotherapy, particularly immune checkpoint blockade (ICB), has drastically improved treatment of metastatic cancer patients. Microbiota composition has been proposed to be one of the reasons for failure or success. ICB works via the activation or reactivation of T cells that are “switched off” by tumor cells or by the tumor microenvironment. Even advanced metastatic disease, previously considered as untreatable, can benefit from cancer immunotherapy. However, still a good proportion of patients does not respond to therapy or acquires resistance during treatment. Some genera or species of bacteria have been associated with treatment response or toxicity, but as the composition of the microbiota is not static, rather, it is very dynamic there is promise that by changing the microbiota composition, or by harnessing the microbiota ‘secrete’ tricks, one can improve treatment efficacy or reduce toxicity. Several players, including diet, prebiotics, probiotics, and postbiotics, have been proposed to shape the microbiota. In this minireview, we summarize very recent data on how to train the microbiota to increase ICB efficacy and reduce toxicity.

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Section: Shaping the Microbiome With The Dietmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Training the microbiota to increase immune checkpoint blockade and to reduce toxicity

Rescigno

2023

Eur J Immunol

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“…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)(9)(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.…”

Section: Introductionmentioning

confidence: 99%

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

Cortez,

Lanzi,

Vahmani

et al. 2023

Oncol Lett

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Ketogenic diets (KDs) are actively being evaluated for their potential anticancer effects. Although KDs are generally considered safe, their safety profile when combined with chemotherapy remains unknown. It is known that a KD enhances the anticancer effect of gemcitabine (2',2'-difluoro-2'-deoxycytidine) in LSL-Kras LSL-G12D/+ Trp53 R172H/+ Pdx-1-Cre (KPC) tumor-bearing mice. In the present study, whether a KD in combination with gemcitabine affected the liver safety profile in KPC mice was evaluated. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; % kcal: 20% fat, 65% carbohydrate, 15% protein) + gemcitabine [control plus gemcitabine group (CG)] or a KD (% kcal: 84% fat, 15% protein, 1% carbohydrate) + gemcitabine [ketogenic plus gemcitabine group (KG)] for two months. After two months of treatment, no significant differences in body weight were observed between CGs and KGs. Moreover, the KD did not significantly alter the serum protein expression levels of liver enzymes, including aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. In addition, the KD did not alter markers of liver-lipid accumulation as well as serum cholesterol and triglyceride levels, compared with the CG-treated group. Upon histologic examination, steatosis was rare, with no notable differences between treatment groups. When examining liver fatty acid composition, KD treatment significantly increased the content of saturated fatty acids and significantly decreased levels of cis-monounsaturated fatty acids compared with the CG. Finally, the KD did not affect liver markers of inflammation and oxidative stress, nor the protein expression levels of enzymes involved in ketone bodies, such as 3-hydroxy-3-methylglutaryl-CoA lyase and hidroximetilglutaril-CoA sintasa, and glucose metabolism, such as hexokinase 2, pyruvate dehydrogenase and phosphofructokinase. In summary, a KD in combination with gemcitabine appears to be safe, with no apparent hepatotoxicity and these data support the further evaluation of a KD as an adjuvant dietary treatment for pancreatic cancer.

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“…In the original version of ( 1 ), there is an error in the abstract. The macronutrient composition of both the ketogenic and control mouse diets was incorrectly reported in the abstract.…”

mentioning

confidence: 99%

Correction: A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

Cortez¹,

Lanzi²,

Hong³

et al. 2022

Cancer Research Communications

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A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

Cited by 12 publications

References 50 publications

Training the microbiota to increase immune checkpoint blockade and to reduce toxicity

Training the microbiota to increase immune checkpoint blockade and to reduce toxicity

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

Correction: A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice

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