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Indomethacin Suppresses Cisplatin-Enriched Stem-Like Breast Cancer Cells Through Modulating MicroRNAs Expression and Stimulating Antitumor Immunity
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  • Norhan Mobark,
  • Nageh Elmahdy,
  • Mohamed Salem,
  • Magda Elsayad,
  • Abdel-aziz Zidan
Norhan Mobark
Tanta University Faculty of Pharmacy
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Nageh Elmahdy
Tanta University Faculty of Pharmacy
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Mohamed Salem
Tanta University Faculty of Science
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Magda Elsayad
Tanta University Faculty of Pharmacy
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Abdel-aziz Zidan
Damanhour University Faculty of Science
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Abstract

Background and Purpose: Cancer resistance to chemotherapy is a clinical dilemma that eventually leads to increased mortality. It is widely accepted that cancer stem cells (CSCs) have a pivotal role in the development of resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown a promise to combat CSCs, thus, we addressed for the first time the effect of indomethacin on cisplatin (CDDP)-resistant murine breast cancer along with the relevant mechanisms. Experimental Approach: The murine mammary adenocarcinoma, Ehrlich ascites carcinoma (EAC) cells, were made resistant by exposure to CDDP and the surviving cells were then analyzed by flow cytometry for the breast CSCs markers (CD44+CD24-). CDDP heavily enriched the CSCs population which was subsequently injected into mice. After induction of tumors, mice were treated with CDDP, or indomethacin, or co-treatment with both drugs, or left untreated. Upon termination of the treatment period, blood samples were collected to measure the percentage of CSCs markers (CD44, CD24, SCa-1) and the immune cells (CD4+, CD62L+, and CD117+). The tumors were excised and analyzed for the relative expression of drug resistance-mediating miRNAs (miR-7, miR-21, miR-22, and miR-145) in addition to histopathological examination. Key Results: Indomethacin drastically diminished the tumorigenicity of CDDP-resistant cells along with enhancing its sensitivity to CDDP which were correlated with its suppressing ability of CD44+CD24- cells and manipulating effect on miRNAs expression. Besides, indomethacin expanded the pool of immune cells that impart antitumor response. Conclusion and Implications: Indomethacin through targeting CSCs may confer better outcome than conventional chemotherapeutics in the treatment of resistant breast cancer.