Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes

Amaral, Maria Eduarda Azambuja; Nery, Laura Roesler; Leite, Carlos Eduardo; Azevedo, Walter Filgueira de; Campos, Maria M.

doi:10.1007/s10637-018-0568-y

Cited by 51 publications

(24 citation statements)

References 63 publications

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“…The combined therapeutic approach is one important strategy to overcome cancer resistance. This strategy involves the simultaneous use of two drugs with different molecular targets [20]. The most important challenge with this approach is to find two synergistic drugs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

et al. 2019

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Etoposide (VP-16) is the topoisomerase 2 (Top2) inhibitor used for treating of glioma patients however at high dose with serious side effects. It induces DNA double-strand breaks (DSBs). These DNA lesions are repaired by non-homologous DNA end joining (NHEJ) mediated by DNA-dependent protein kinase (DNA-PK). One possible approach to decrease the toxicity of etoposide is to reduce the dose while maintaining the anticancer potential. It could be achieved through combined therapy with other anticancer drugs. We have assumed that this objective can be obtained by (1) a parallel topo2 α inhibition and (2) sensitization of cancer cells to DSBs. In this work we investigated the effect of two Top2 inhibitors NK314 and VP-16 in glioma cell lines (MO59 K and MO59 J) sensitized by DNA-PK inhibitor, NU7441. Cytotoxic effect of VP-16, NK314 alone and in combination on human glioblastoma cell lines, was assessed by a colorimetric assay. Genotoxic effect of anticancer drugs in combination with NU7441 was assessed by comet assay. Cell cycle distribution and apoptosis were analysed by flow cytometry. Compared with VP-16 or NK314 alone, the combined treatment significantly inhibited cell proliferation. Combination treatment was associated with a strong accumulation of DSBs, modulated cell cycle phases distribution and apoptotic cell death. NU7441 potentiated these effects and additionally postponed DNA repair. Our findings suggest that NK314 could overcome resistance of MO59 cells to VP-16 and NU7441 could serve as sensitizer to VP-16/ NK314 combined treatment. The combined tripartite approach of chemotherapy could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the anticancer effect to treat human glioma cells. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than mono therapy or dual therapy to treat and increase the survival of the glioblastoma patients.

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Section: Discussionmentioning

confidence: 99%

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

et al. 2019

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“…In addition, aspirin may also act through other pathways to exert its chemopreventive properties involving inflammation, cyclooxygenase- (COX-) 2, platelets, hormones, or PI3 kinase [ 33 ]. One of the most studied aspirin anticancer mechanisms is the partially downregulated COX-2 expression in many types of breast cancer cells, including MCF-7, MDA-MB-231, and SK-BR-3, contributing to inhibition of cancer cell proliferation [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Aspirin Disrupts the Crosstalk of Angiogenic and Inflammatory Cytokines between 4T1 Breast Cancer Cells and Macrophages

Hsieh

Wang

2018

Mediators of Inflammation

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The tumor microenvironment is rich in multiple cell types that influence tumor development. Macrophages infiltrate tumors, where they are the most abundant immune cell population and secrete a number of cytokines. Aspirin acts as a chemopreventive agent against cancer development. This study investigated whether aspirin regulates crosstalk between breast cancer cells and macrophages. To study these interactions in a tumor microenvironment, a conditioned media was employed using 4T1 breast cancer cells cultured in RAW 264.7 cell-conditioned medium (RAW-CM), and a cocultured model of both cells was used. When 4T1 cells were cultured in the RAW-CM, there were increases in cell viability and secretion of the cytokines VEGF, PAI-1, TNF-α, and IL-6. Treatment with aspirin inhibited 4T1 cell growth and migration and MCP-1, PAI-1, and IL-6 production. In the coculture of both cells, aspirin inhibited secretion of MCP-1, IL-6, and TGF-β. Furthermore, aspirin significantly decreased the M2 macrophage marker CD206, but increased M1 marker CD11c expression. In summary, aspirin treatment inhibited the crosstalk of 4T1 and RAW 264.7 cells through regulation of angiogenic and inflammatory mediator production and influenced the M1/M2 macrophage subtype. This highlighted that aspirin suppresses the tumor favorable microenvironment and could be a promising agent against triple-negative breast cancer.

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“…MCF7, SK-BR-3, MDA-MB-231, [173] Chrysin Synergistic growth inhibitory effects due to suppression of hTERT and cyclin D1 gene expression T47D [174] Curcumin Inhibition of tumor proliferation and growth associated with reduced VEGF expression and angiogenesis, induction of p53 independent apoptosis, and activation of Th2 related immune response with no toxicity. EMT6/P cells, BALB/c mice inoculated with EMT6/P cells [175] Combination of PEGylated PLGA nanoparticle co-encapsulated metformin and curcumin exhibited dosage dependent toxicity and synergistic antiproliferative effect causing significant cell cycle/growth arrest in the cancer cells.…”

Section: T1 Balb/c Mice Inoculated With 4t1 Cells [172]mentioning

confidence: 99%

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

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Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

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Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes

Cited by 51 publications

References 63 publications

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

Aspirin Disrupts the Crosstalk of Angiogenic and Inflammatory Cytokines between 4T1 Breast Cancer Cells and Macrophages

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

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