Abstract
Many clinical trials are beginning to assess the effectiveness of compounds known to regulate autophagy in patients receiving anti-cancer chemotherapy. However, autophagy inhibition, through exogenous inhibitors, or activation, through starvation, has revealed conflicting roles in cancer management and chemotherapeutic outcome. This study aimed to assess the effect of amino acid starvation on doxorubicin-treated breast cancer cells by assessing the roles of autophagy and apoptosis. An in vitro breast cancer model consisting of the normal breast epithelial MCF12A and the metastatic breast cancer MDAMB231 cells was used. Apoptotic and autophagic parameters were assessed following doxorubicin treatments, alone or in combination with bafilomycin, ATG5 siRNA or amino acid starvation. Inhibition of autophagy, through ATG5 siRNA or bafilomycin treatment, increased caspase activity and intracellular doxorubicin concentrations in MCF12A and MDAMB231 cells during doxorubicin treatment. While amino acid starvation increased autophagic activity and decreased caspase activity and intracellular doxorubicin concentrations in MCF12A cells, no changes in autophagic parameters or caspase activity were observed in MDAMB231 cells. Our in vivo data showed that 24 h protein starvation during high dose doxorubicin treatment resulted in increased survival of tumor-bearing GFP-LC3 mice. Results from this study suggest that short term starvation during doxorubicin chemotherapy may be a realistic avenue for adjuvant therapy, especially with regards to the protection of non-cancerous cells. More research is however, needed to fully understand the regulation of autophagic flux during starvation.
Highlights
Solid tumors make up the majority of all human cancers
Dox elicits an autophagic response in breast cancer cells (Akar et al, 2008), as well as in sarcoma cell lines (Martinez-Lopez et al, 2016)
It was reported that 2-deoxy-glucose preserved ATP content and contributed to the cytoprotection of rat cardiomyocytes treated with 1 μM Dox (Chen et al, 2011)
Summary
Solid tumors make up the majority of all human cancers. Nutrient Starvation and Chemotherapy of patients (Heilbronn and Ravussin, 2005) and facilitate tumor suppression (Kritchevsky, 2003). The application of short term starvation protocols in patients receiving high doses of chemotherapy has proven successful in reducing side effects in these patients (Safdie et al, 2009). In a cell culture and neuroblastoma mouse xenograft model, normal cells placed on a similar starvation protocol were shown to benefit from differential protection compared to cancer cells during high dose chemotherapy regimens (Raffaghello et al, 2008). Tumor cell death was not compromised by the starvation protocol. The underlying mechanisms responsible for this differential protection of non-cancer cells are not yet fully understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
