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

AI Article Synopsis

  • Chemotherapy is crucial for treating triple negative breast cancer (TNBC), but its effectiveness can be hampered by drug toxicity and resistance, motivating research into methods to enhance treatment efficacy, such as fasting.
  • Short-term starvation (STS) combined with chemotherapy was found to increase cancer cell death and reactive oxygen species (ROS) levels, leading to more DNA damage in TNBC cells than in normal cells, while also negatively impacting mitochondrial function and altering metabolism.
  • This study provides insights into the mechanisms by which STS can enhance chemotherapy sensitivity in TNBC and validates the safety of combining a low-calorie diet with chemotherapy in mouse models, suggesting potential clinical relevance for patients.

Article 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 HDCFDA 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9983166PMC
http://dx.doi.org/10.1186/s12967-023-03935-9DOI Listing

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