بيانات النشر: UmeÃ¥ universitet, Institutionen för integrativ medicinsk biologi (IMB)
Umeå universitet, Institutionen för fysiologisk botanik
Umeå universitet, Umeå Centre for Microbial Research (UCMR)
Umeå universitet, Institutionen för molekylärbiologi (Medicinska fakulteten)
Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
2nd Department of Pathology, “Attikon†University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
2nd Department of Internal Medicine, Athens Naval and Veterans Hospital, Athens, Greece
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
Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece
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
Swedish Metabolomics Centre, Umeå University, Umeå, Sweden
Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
Centre for Basic Research, Bioimaging Unit, Biomedical Research Foundation, Academy of Athens, Athens, Greece
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
Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), NCI, NIH, MD, Bethesda, United States
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
Department of Paediatrics, University of Patras Medical School, General University Hospital, Patras, Greece
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
نبذة مختصرة : 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 ...
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