Synergistic Anti-proliferative Effects of Metformin and Silibinin Combination on T47D Breast Cancer Cells via hTERT and Cyclin D1 Inhibition

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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“…Downregulation of hTERT and cyclin D1 was observed with the combinatorial therapeutic approach. T47D [192] Spautin-1…”

Section: T1 Cells Balb/c Mice Inoculated With 4t1 Cells [191]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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“…The combination of 17‐AAG with targeted antibodies, signaling pathway inhibitors, proteasome inhibitors, and conventional cytotoxic drugs paves the way for novel dual‐mode platforms for cancer therapy (Lu, Xiao, Wang, & Ruden, ). The outcome of such combinations may enhance therapeutic effects as a result of either their additive drug action or as a result of their synergistic interaction (Chatran et al., ; Jafari‐Gharabaghlou et al., ; Maasomi et al., ).…”

Section: ‐Aag In Preclinical Research: Focus On Combination Therapymentioning

confidence: 99%

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

et al. 2019

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Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins. There have been several preclinical studies of 17‐AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases of clinical trials show that 17‐AAG can be given safely at biologically active dosages with mild toxicity. Even though 17‐AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials‐based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17‐AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17‐AAG.

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“…Metformin (MET) (1,1-hydrochloride) is a biguanide originated from French lilac or goat's rue (Galega officinalis), which was most widely prescribed as an oral antihyperglycemic agent particularly for managing type 2 diabetes mellitus [4].…”

Section: Introductionmentioning

confidence: 99%

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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Synergistic Anti-proliferative Effects of Metformin and Silibinin Combination on T47D Breast Cancer Cells via hTERT and Cyclin D1 Inhibition

Abstract: The results provide evidence that synergistic antiproliferative effects of MET and SIL, linking to the down-regulation of Cyclin D1 and hTERT genes, and propose that MET+SIL may have therapeutic value in breast cancer therapy.

Cited by 52 publications

References 35 publications

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

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

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

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

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