Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis

Falah, Rabah Rashad; Talib, Wamidh H.; Shbailat, Seba Jamal

doi:10.1177/1758834016687482

Cited by 76 publications

(48 citation statements)

References 75 publications

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“…Together, MTFN and CURC appear to have converging points to synergize in halting tumorigenicity as a whole but also each can affect specific molecules or pathways within cancer cells. Co-treatment with MTFN and CURC indeed inhibits cancer growth, metastasis, angiogenesis in-vitro and in vivo [33], modulates immune system, and induces apoptosis independent from p53 in BC [34].…”

Section: Discussionmentioning

confidence: 99%

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Afzali

Nayeri

Minuchehr

et al. 2019

Preprint

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Nearly 16% of people with breast cancer (BC) have Diabetes Mellitus type 2 (DM2) and are at a higher risk of death worldwide. Their common regulatory factors and functional mechanisms can be targeted applying multi-target drugs including Metformin (MTFN) and Curcumin (CURC). In this study, we used in-silico approaches to study the potential underlying mechanisms of this co-treatment strategy on BC and DM2 in order to introduce novel therapeutic targets.The total number of 48 shared differentially expressed genes (17 up-regulated and 31 down-regulated) were identified through establishing diseases' protein-protein network and BC RNA-sequencing expression data. The integration of functional clustering and pathway analyses revealed that the most involved cellular pathways and processes are regard to cells' proliferation, death, migration, and response to external stimulus. Afterwards, the MTFN/CURC correlation and co-treatment optimization was probed through response surface methodology (RSM) based on MCF7 cell line and confirmed by MDA-MB-231. Combination index calculation by MTT viability assay proved supportive effects on both cell lines. The superior apoptotic potential of co-treatment compared to single treatments was shown on inhibition of MCF7 proliferation and induction of cell death demonstrated by cell body co-staining and flow cytometry as well as gene expression analysis via RT-PCR. Furthermore, wound-healing scratch assay showed that this co-treatment has a slightly higher effect on migration inhibition compared to single treatments.In conclusion, our study used in-silico and in-vitro approaches and introduced a potential regulatory panel between BC and DM2. We also provided a linear model and equation that show the positive relation of drugs' co-treatment. The proposed co-treatment strategy successfully controlled the biological processes under investigation. METHODS Identification and validation of overlapped DEGs between BC and DM2The STRING disease network importer of Cytoscape 3.6 was used to establish the PPI networks of BC and DM2 with ultimate number of proteins (2000 nodes) and 0.7 as the minimum interaction score. The networks were merged together to find the overlapped factors and subsequently, filtered by BC differentially expressed genes (DEGs) of The Cancer Genome Atlas (TCGA) database. TCGA database contains the RNA-sequencing (RNA-seq) expression data of 33 different types of human cancers. In this study, BC RNA-seq raw data of 224 samples (112 cancerous tissues and 112 adjacent normal ones) was downloaded and normalized using TCGAbiolinks package of R v3.5.2 software. To identify the (DEGs) the criteria of FDR < 0.05 and |logFC| > 1 were applied. Functional Annotation Clustering and Pathway AnalysisTo understand the biological meaning behind the obtained DEGs in groups, Functional Annotation Clustering tool of David 6.7 database, based on Kappa statistics and fuzzy heuristic clustering algorithms, was used to make the ontology report easier to follow [23]. Each cluster contains Gene Ont...

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Section: Discussionmentioning

confidence: 99%

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Afzali

Nayeri

Minuchehr

et al. 2019

Preprint

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“…Dosage range between 50 ug/kg to 200mg/kg were effectively inhibit breast cancer growth as reported in previous studies on various animal model species [11], [21], [22]. However, curcumin dosage of 50mg/kg was used to Balb/c mice induced EMT6 breast cancer tumor size [12]. Therefore this study is used as reference.…”

Section: Selection Of Curcumin Dosementioning

confidence: 91%

“…The tumor growth in female CD1 nude mice suppressed by the combination treatment of curcumin (200mg/kg/day) and epigallocethun gallate (25mg/kg/day) for 10 weeks [11]. Further, study reported that combination of curcumin (50mg/kg) and metformin (80mg/kg) in 14 days showed the highest significant reduction in the tumour size [12]. While the combination of taxol with curcumin in the BT-474 xenograft model had an antitumour effect comparable with taxol and herceptin treatment [10].…”

Section: Introductionmentioning

confidence: 97%

Antitumor Effect of Fever Range Whole Body Hyperthermia with Curcumin in Breast Cancer-induced Mice

2019

ijrte

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Breast cancer is a complex and heterogeneous disease and also one of the major cancer types among female worldwide. Fever range whole-body hyperthermia and curcumin as a single treatment have been tested against breast cancer and showed some promising anti-tumor effect. However, their combination as an effective anti- tumor treatment against breast cancer has never been explored. The effects of combined wholebody fever range hyperthermia and curcumin on tumor growth was examined in this study. Mice were inoculated with EMT6 cells subcutaneously and allocated to 4 treatment groups: (i) control (control), (ii) curcumin (50mg/kg bodyweight), (iii) twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes, (iv) a combination of curcumin (50mg/kg bodyweight) and twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes. Following treatment, mice body weight and tumor volume were measured. The greatest tumor growth inhibition exhibited in combination treatment (68.45%, p<0.05) and showed no general toxicity. As conclusion, the combination treatment can be a potential anti-tumor treatment of breast cancer.

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“…When utilized in HNSCC, the anticarcinogenic properties of curcumin include induction of apoptosis, cell cycle arrest, radiosensitivity, and chemotherapy sensitization . Dual treatment with both curcumin and metformin has been reported in hepatocellular carcinoma, pancreatic cancer cells, and breast cancer with the results suggesting synergistic effects. Combined treatment with metformin and curcumin is also thought to enhance chemoprevention properties, in vitro and in vivo, in oral cancer …”

Section: Introductionmentioning

confidence: 99%

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

Lindsay

Kostiuk

Conrad

et al. 2019

Molecular Carcinogenesis

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The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)‐mediated oncogenesis. Unfortunately, a growing number of HPV‐positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well‐tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first‐line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well‐tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+ and HPV‐negative (−) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV− HNSCC cell lines. The curcumin effects appear more pronounced in the HPV− cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.

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Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis

Cited by 76 publications

References 75 publications

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Antitumor Effect of Fever Range Whole Body Hyperthermia with Curcumin in Breast Cancer-induced Mice

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells

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