Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth.

TitleKetogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth.
Publication TypeJournal Article
Year of Publication2022
AuthorsYang, L, TeSlaa, T, Ng, S, Nofal, M, Wang, L, Lan, T, Zeng, X, Cowan, A, McBride, M, Lu, W, Davidson, S, Liang, G, Oh, TGyu, Downes, M, Evans, R, Von Hoff, D, Guo, JYanxiang, Han, H, Rabinowitz, JD
JournalMed (N Y)
Volume3
Issue2
Pagination119-136
Date Published2022 02 11
ISSN2666-6340
KeywordsAnimals, Carbohydrates, Diet, Ketogenic, Humans, Mice, NAD, Pancreatic Neoplasms, Randomized Controlled Trials as Topic
Abstract

<p><b>Background: </b>Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer.</p><p><b>Methods: </b>Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including H- and C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry.</p><p><b>Findings: </b>Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system.</p><p><b>Conclusions: </b>Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445).</p>

DOI10.1016/j.medj.2021.12.008
Alternate JournalMed (N Y)
PubMed ID35425930
PubMed Central IDPMC9004683
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA237347 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R37 DK057978 / DK / NIDDK NIH HHS / United States
R50 CA211437 / CA / NCI NIH HHS / United States
R01 DK057978 / DK / NIDDK NIH HHS / United States