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

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

Pateras, Ioannis S. (författare): 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Williams, Chloe (författare): Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)

Gianniou, Despoina D. (författare): Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

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Margetis, Aggelos T. (författare): 2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece

Avgeris, Margaritis (författare): Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, “P. & A. Kyriakou” Children’s Hospital, Athens, Greece; Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

Rousakis, Pantelis (författare): Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece

Legaki, Aigli-Ioanna (författare): Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Mirtschink, Peter (författare): Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

Zhang, Wei (författare): Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre, Umeå University, Umeå, Sweden

Panoutsopoulou, Konstantina (författare): Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

Delis, Anastasios D. (författare): Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece

Pagakis, Stamatis N. (författare): Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece

Tang, Wei (författare): Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States; Data Science & Artificial Intelligence, R&D, AstraZeneca, MD, Gaithersburg, United States

Ambs, Stefan (författare): Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States

Warpman Berglund, Ulrika (författare): Karolinska Institutet

Helleday, Thomas (författare): Karolinska Institutet

Varvarigou, Anastasia (författare): Department of Paediatrics, University of Patras Medical School, General University Hospital, Patras, Greece

Chatzigeorgiou, Antonios (författare): Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

Nordström, Anders (författare): Umeå universitet,Institutionen för fysiologisk botanik,Swedish Metabolomics Centre, Umeå University, Umeå, Sweden

Tsitsilonis, Ourania E. (författare): Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece

Trougakos, Ioannis P. (författare): Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

Gilthorpe, Jonathan D. (författare): Umeå universitet,Institutionen för integrativ medicinsk biologi (IMB)

Frisan, Teresa, 1967- (författare): Umeå universitet,Umeå Centre for Microbial Research (UCMR),Institutionen för molekylärbiologi (Medicinska fakulteten),Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)

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2023-03-03
2023
Engelska.
Ingår i: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21:1

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Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

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

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