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Archives of Breast Cancer، جلد ۱۱، شماره ۲، صفحات ۱۵۹-۱۷۱
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عنوان انگلیسی Acquisition of Doxorubicin Resistance Induces Breast Cancer Cell Migration and Epithelial-Mesenchymal Transition that are Reversed by Shikonin-Metformin Synergy: Dox resistance and BC cell migration
چکیده انگلیسی مقاله Background: Drug resistance is a major challenge in cancer chemotherapy. Methods: By adopting an appropriately timed strategy, we generated MCF-7 cell sublines resistant to serial doses of doxorubicin (DOX). Our higher-dose sublines showed more stability in resistance and were, therefore, subjected to further analyses. We tested the consistency of drug resistance by comparing sublines with control groups for growth and migration capacities. Molecular analyses monitored expression changes, CD44/CD24 ratios, and DOX binding to key molecules. The reverting impact of shikonin (SHKN) and metformin (MTFN) on DOX resistance was examined. Results. The resistant sublines grew parallel to or even faster than WT MCF-7 cells and showed a larger and more rounded morphology. The consistency of their drug resistance and invasive potential was demonstrated over time using serial doses of DOX. Real-time PCR revealed upregulation of genes involved in cell growth and survival, drug resistance, migration/invasion, and epithelial-mesenchymal transition and, conversely, downregulation of pro-apoptotic, anti-chemoresistance, and tumor suppressor genes. SHKN-MTFN co-treated resistant cells showed significantly lower CD44/CD24 ratios, less aggressiveness, and reduced survival and migration rates but enhanced apoptosis. SHKN’s affinity to CYP1A and TOP2A demonstrated the importance of these interactions and the compounds’ capacity to compete with DOX. Conclusion: Acquisition of DOX resistance increases tumorigenic properties of cancer cells, whereas synergy between selective anti-tumorigenic compounds re-sensitizes resistant cells by reverting cellular pathways that favor or follow resistance. Our findings suggest that this reversal is supported by competing reactions that deprive DOX of binding to its target molecules.
کلیدواژه‌های انگلیسی مقاله breast cancer,drug resistance,doxorubicin,shikonin,metformin
نویسندگان مقاله | Atlas Keshandehghan
National Institute of Genetic Engineering and Biotechnology, Tehran, Iran


| Abolfazl Rostamian Tabari
National Institute of Genetic Engineering and Biotechnology, Tehran, Iran


| Yasin Panahi
Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran


| Mossa Gardaneh
Genomedicx Co., Richmond Hill, Ontario, Canada
نشانی اینترنتی https://archbreastcancer.com/index.php/abc/article/view/891
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کد مقاله (doi) 10.32768/abc.2024112159-171
زبان مقاله منتشر شده en
موضوعات مقاله منتشر شده
نوع مقاله منتشر شده Original Article
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