Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ioannis S. Pateras - , National and Kapodistrian University of Athens (Author)
  • Chloe Williams - , Umeå University (Author)
  • Despoina D. Gianniou - , National and Kapodistrian University of Athens (Author)
  • Aggelos T. Margetis - , Hellenic Naval Academy (Author)
  • Margaritis Avgeris - , National and Kapodistrian University of Athens (Author)
  • Pantelis Rousakis - , National and Kapodistrian University of Athens (Author)
  • Aigli Ioanna Legaki - , National and Kapodistrian University of Athens (Author)
  • Peter Mirtschink - , University Medicine (Faculty of Medicine and University Hospital), Institute of Clinical Chemistry and Laboratory Medicine, German Center for Diabetes Research (DZD e.V.) (Author)
  • Wei Zhang - , Umeå University (Author)
  • Konstantina Panoutsopoulou - , National and Kapodistrian University of Athens (Author)
  • Anastasios D. Delis - , Academy of Athens (Author)
  • Stamatis N. Pagakis - , Academy of Athens (Author)
  • Wei Tang - , National Cancer Institute (NCI), AstraZeneca (Author)
  • Stefan Ambs - , National Cancer Institute (NCI) (Author)
  • Ulrika Warpman Berglund - , Karolinska Institutet (Author)
  • Thomas Helleday - , Karolinska Institutet, University of Sheffield (Author)
  • Anastasia Varvarigou - , University of Patras (Author)
  • Antonios Chatzigeorgiou - , National and Kapodistrian University of Athens, University Hospital Carl Gustav Carus Dresden, Institute for Clinical Chemistry and Laboratory Medicine (Author)
  • Anders Nordström - , Umeå University (Author)
  • Ourania E. Tsitsilonis - , National and Kapodistrian University of Athens (Author)
  • Ioannis P. Trougakos - , National and Kapodistrian University of Athens (Author)
  • Jonathan D. Gilthorpe - , Umeå University (Author)
  • Teresa Frisan - , Umeå University (Author)

Abstract

Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized. Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model. Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model. Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

Details

Original languageEnglish
Article number169
JournalJournal of translational medicine
Volume21
Issue number1
Publication statusPublished - Dec 2023
Peer-reviewedYes

External IDs

PubMed 36869333

Keywords

Sustainable Development Goals

Keywords

  • Breast cancer, Caloric restriction, Fasting, Metabolic reprogramming, Mitochondria, Oncological treatment, Oxidative stress, Reactive oxygen species, Starvation, Triple negative breast cancer