Effect of metformin on apoptosis induction in ovarian cancer cells

Rogalska, Aneta; Forma, Ewa; Ciesielski, Piotr; Bryś, Magdalena; Krześlak, Anna; Marczak, Agnieszka

doi:10.5114/pm.2014.43817

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…EGFR expression with a greater capacity to invade than OVCAR-3. Rogalska et al [15] and Faramarzi et al [16] both demonstrated that the IC50 of MTF when treating SKOV-3 cells was 14mM and 14.92mM respectively, similar to our data. Another study by Huo et al [17] also showed that MTF (0-20mM) had an inhibitory effect on the proliferation of SKOV-3 cells Our study marks a significant contribution as the first to reveal the impact of combining MTF and SIM on the proliferation and viability of ovarian cancer cells.…”

Section: Plos Onesupporting

confidence: 91%

Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells

Mikhael,

Kurdi,

Khoueiry-Zgheib

et al. 2024

PLoS ONE

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Background Ovarian Cancer (OC) stands as the most lethal gynecological malignancy, presenting an urgent clinical challenge in the quest to improve response rates. One approach to address this challenge is through drug repurposing, exemplified by the investigation of metabolic-modulating drugs such as Metformin (MTF) and Simvastatin (SIM). This study aims to explore the molecular mechanisms contributing to the potential synergistic anti-cancer effects between MTF and SIM on ovarian cancer cells. Methods We assessed the effects of the combination on the proliferation and viability of two cell lines OVCAR-3 and SKOV-3. IC50 concentrations of MTF and SIM were determined using a proliferation assay, followed by subtoxic concentrations to explore the potential synergistic effects on the viability of both cell lines. Transcriptomic analysis was conducted on OVCAR-3 treated cells, and the findings were validated by assessing the expression levels of differentially expressed genes (DEGs) through real-time PCR in both cell lines SK-OV-3 and OVCAR-3. Results Cytotoxicity analysis guided the selection of treatment concentrations as such MTF 10 mM and SIM 5 μM. The combined treatment of MTF and SIM demonstrated a synergistic inhibition of proliferation and viability in both cell lines. In OVCAR-3, exclusive identification of 507 DEGs was seen in the combination arm. Upregulation of FOXO3, RhoA, and TNFα, along with downregulation of PIK3R1, SKP2, and ATP6V1D levels, was observed in OVCAR-3 treated cells. Real-time PCR validation confirmed the consistency of expression levels for the mentioned DEGs. Conclusion Our data strongly supports the presence of synergy between MTF and SIM in OC cells. The combination’s effect is associated with the dysregulation of genes in the key regulators AMPK and mTOR alongside other interconnected pathways.

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Section: Plos Onesupporting

confidence: 91%

Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells

Mikhael,

Kurdi,

Khoueiry-Zgheib

et al. 2024

PLoS ONE

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“…40 P53 was reported to be required for MET-induced growth inhibition, senescence, and apoptosis in breast cancer cells. 41,42 In addition, Liu et al 43 reported that DOX caused early activation of P53 in tumor cells that was followed by caspase-3 activation and DNA fragmentation. DOX was reported to induce apoptosis in human colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway

et al. 2017

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Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

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“…Rogalska et al showed that MET can induce apoptosis in an AMPK-independent manner and arrest cell cycle in the S and G2/M stages in OVCAR-3 and OVCAR-4 cell lines. In OVCAR-3 and OVCAR-4 cells, apoptosis was induced through activating caspase 3/7, up-regulating Bax and Bad, and downregulating bcl-2 and bcl-xL [49]. Moreover, it was found that alteration in the BIRC5 mRNA expression was related to apoptosis induction in SKOV-3 ovarian cancer cells treated with MET.…”

Section: Gene Expression Analysismentioning

confidence: 97%

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

Faramarzi

Dadashpour

Sadeghzadeh

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Metformin (MET) has received considerable attention in recent years for its anticancer potential activities. However, short half-life and weak bioavailability of MET limited its use as a chemotherapeutic agent. The present study is intended to evaluate the efficiency of PLGA-PEG as a nano-carrier for MET to increase anticancer effects on SKOV3 ovarian carcinoma cells. MET-loaded PLGA-PEG nanoparticles (NPs) were characterized through Dynamic Light Scattering (DLS), Fourier-transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FE-SEM). Anti-proliferative and apoptotic effects of nanoformulated MET were evaluated using MTT and flow-cytometric assays, respectively. Also, real-time polymerase chain reaction (Real-Time PCR) was used to determine the gene expression levels of apoptotic genes, p53 and hTERT. Evaluation of cytotoxicity showed that MET-NPs had more cytotoxicity than free MET in a time-and dose-dependent manner. The nuclei fragmentation and the percentage of apoptotic cells induced by MET-NPs were significantly higher than free MET. Also, it was found that MET-NPs triggered more cell cycle arrest at sub-G1 checkpoint than free MET. Compared to MET treated cells, the mRNA expression levels of apoptotic genes, as well as p53 and hTERT were significantly altered in MET-NPs treated cells. In conclusion, it is supposed that nano-encapsulation of MET into polymeric PLGA-PEG NPs may be a convenient drug delivery system to enhance its anticancer effects for ovarian cancer therapy.

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Effect of metformin on apoptosis induction in ovarian cancer cells

Cited by 6 publications

References 35 publications

Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells

Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

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