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Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chittaranjan, Suganthi Bortnik, Svetlana Dragowska, Wieslawa H. Xu, Jing Abeysundara, Namal Leung, Amy Qui Ling Go, Nancy Erro Devorkin, L. Weppler, Sherry Anne. Gelmon, Karen Yapp, Donald Tshin Tsun Bally, Marcel Gorski, Sharon M. |
| Copyright Year | 2014 |
| Abstract | PURPOSE Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines. EXPERIMENTAL DESIGN We used in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo. RESULTS We demonstrated that epirubicin induced autophagic flux in TNBC cells. Epirubicin-resistant lines exhibited at least 1.5-fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of epirubicin with the autophagy inhibitor hydroxychloroquine resulted in a significant reduction in tumor growth compared with monotherapy with epirubicin. CONCLUSION Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and -resistant TNBC and may be an effective new treatment strategy for this disease. |
| Starting Page | 111 |
| Ending Page | 132 |
| Page Count | 22 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/early/2014/04/10/1078-0432.CCR-13-2060.full.pdf |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/20/12/3159.full.pdf |
| PubMed reference number | 24721646v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-13-2060 |
| DOI | 10.1158/1078-0432.ccr-13-2060 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Volume Number | 20 |
| Issue Number | 12 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Anthracyclines Autophagy Cell Survival Cultured Cell Line Disease Progression Epirubicin Estrogen Receptors Estrogens Growth Factor Receptors Hydroxychloroquine Mammary Neoplasms Receptors, Progesterone Triple Negative Breast Neoplasms estrogen receptor alpha, human |
| Content Type | Text |
| Resource Type | Article |
