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

Lifeng Yang, Tara TeSlaa, Serina Ng, Michel Nofal, Lin Wang, Taijin Lan, Xianfeng Zeng, Alexis Cowan, Matthew McBride, Wenyun Lu, Shawn Davidson, Gaoyang Liang, Tae Gyu Oh, Michael Downes, Ronald Evans, Daniel Von Hoff, Jessie Yanxiang Guo, Haiyong Han, Joshua D. Rabinowitz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer. Methods: 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 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry. Findings: 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. Conclusions: 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). Funding: NIH R01CA163591, R50CA211437, R01CA237347-01A1, R01DK057978; NJCCR; NJHF; SU2C-AACR-DT-20-16; ACS134036-RSG-19-165-01-TBG; Rutgers Busch Biomedical Grant; Freeberg Foundation; Copley Foundation; Ludwig Cancer Research.

Original languageEnglish (US)
Pages (from-to)119-136.e8
JournalMed
Volume3
Issue number2
DOIs
StatePublished - Feb 11 2022

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Keywords

  • NADH/NAD
  • Pre-clinical research
  • chemotherapy
  • ketogenic diet
  • ketone metabolism
  • pancreatic cancer
  • reactive oxygen species

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