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Int J Mol Sci ; 21(16)2020 Aug 12.
Article in English | MEDLINE | ID: mdl-32806648

ABSTRACT

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.


Subject(s)
Cisplatin/pharmacology , Neoplastic Stem Cells/pathology , Triple Negative Breast Neoplasms/pathology , Tumor Hypoxia/drug effects , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gefitinib/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Metformin/pharmacology , Triple Negative Breast Neoplasms/genetics , Up-Regulation/drug effects , Up-Regulation/genetics
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