Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.565915/full |
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| author | Mark Thomas Tanja Davis Theo Nell Balindiwe Sishi Anna-Mart Engelbrecht Anna-Mart Engelbrecht |
| author_facet | Mark Thomas Tanja Davis Theo Nell Balindiwe Sishi Anna-Mart Engelbrecht Anna-Mart Engelbrecht |
| author_sort | Mark Thomas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T14:24:28Z |
| format | Article |
| id | doaj.art-d75bb093e8ca452a9156e52676acf757 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-12T14:24:28Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-d75bb093e8ca452a9156e52676acf7572022-12-22T00:21:44ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-10-01810.3389/fcell.2020.565915565915Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell DeathMark Thomas0Tanja Davis1Theo Nell2Balindiwe Sishi3Anna-Mart Engelbrecht4Anna-Mart Engelbrecht5Department of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South AfricaDepartment of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South AfricaDepartment of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South AfricaDepartment of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South AfricaDepartment of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South AfricaAfrican Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South AfricaMany 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.https://www.frontiersin.org/article/10.3389/fcell.2020.565915/fullnutrient starvationamino acidsdoxorubicinbreast cancersensitization |
| spellingShingle | Mark Thomas Tanja Davis Theo Nell Balindiwe Sishi Anna-Mart Engelbrecht Anna-Mart Engelbrecht Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death Frontiers in Cell and Developmental Biology nutrient starvation amino acids doxorubicin breast cancer sensitization |
| title | Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death |
| title_full | Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death |
| title_fullStr | Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death |
| title_full_unstemmed | Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death |
| title_short | Amino Acid Starvation Sensitizes Resistant Breast Cancer to Doxorubicin-Induced Cell Death |
| title_sort | amino acid starvation sensitizes resistant breast cancer to doxorubicin induced cell death |
| topic | nutrient starvation amino acids doxorubicin breast cancer sensitization |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.565915/full |
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