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

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.

Prognostic Worth of Nrf2/BACH1/HO-1 Protein Expression in the Development of Breast Cancer

“…Therefore, functional Nrf2 activity in human breast carcinoma is reflected by nuclear Nrf2 immunoreactivity, and its relatively wide distribution indicates the relevance of activated Nrf2 signaling pathway in breast cancer. Aberrant Nrf2 expression is associated with increased resistance to therapy in breast cancer, implying that Nrf2 genes are downregulated in breast cancer after starvation, which is associated with increased ROS levels [ 7 , 17 ]. Hyperactivation of Nrf2 has been reported to upregulate glucose‐6‐phosphate dehydrogenase/HIF‐1α/Notch1 signaling to promote migration and metastasis of breast cancer cells [ 18 ].…”

Effects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential

“… 14 This heightened sensitivity has been observed in various contexts, including the enhancement of gemcitabine efficacy in mice with prostate cancer xenografts and the increased efficacy of chemotherapy in triple-negative breast cancer via the upregulation of ROS. 251 , 252 FMD combined with vitamin C can potentially increase the effectiveness of chemotherapy for treating KRAS-mutant cancer cells by reversing the vitamin C-induced upregulation of HO-1 and ferritin. 253 Furthermore, when combined with a ferroptosis inducer, FMD can effectively eliminate slow-cycling, chemotherapy-resistant cells, suggesting a potential strategy for enhancing the sensitivity of certain difficult-to-treat cancers to chemotherapy through dietary interventions.…”

The Micro-Immunotherapy Medicine 2LPAPI® Displays Immune-Modulatory Effects in a Model of Human Papillomavirus Type-16 L1-Protein Capsid-Treated Human Peripheral Blood Mononuclear Cells and Antiproliferative Effects in a Model of Cervical Cancer Cells

“…The rationale behind the second part of this study relies on two main pieces of evidence: (i) serum deprivation is known to preferentially sensitize cancer cells to chemotherapeutic agents compared to near normal cells [42], and (ii), the posology of 2LPAPI requires a fasted state. Thus, we wanted to assess the effects of 2LPAPI on HeLa cell proliferation under serum starvation conditions.…”