Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51.
Background: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for...
| Publicado en: | Breast Cancer Research Vol. 21; no. 1 |
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| Autores principales: | , , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
BioMed Central
10/22/2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=139273776&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 139273776 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 10/22/2019 vid: 21 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 139273776 139273776 NLM31640742 10.1186/s13058-019-1204-2 NLM31640742 139273776 ppct: 1 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51. aug: au: Lee, Jung Ok Kang, Min Ju Byun, Won Seok Kim, Shin Ae Seo, Il Hyeok Han, Jeong Ah. Moon, Ji Wook Kim, Ji Hae Kim, Su Jin Lee, Eun Jung In Park, Serk Park, Sun Hwa Kim, Hyeon Soo affil: Department of Anatomy, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, Republic of Korea sug: subj: Breast Neoplasms Metabolism Cisplatin Pharmacodynamics Drug Resistance, Neoplasm Metformin Pharmacodynamics Cell Physiology Drug Effects Cisplatin Administration and Dosage Animals Metformin Administration and Dosage Breast Neoplasms Female Antineoplastic Agents, Combined Pharmacodynamics Breast Neoplasms Drug Therapy Mice Drug Synergism Antineoplastic Agents Pharmacodynamics Genes Drug Effects Breast Neoplasms Pathology Antineoplastic Agents Administration and Dosage Cell Line, Tumor Cell Movement Drug Effects Female ab: Background: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported.Methods: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed.Results: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo.Conclusions: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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