Glibenclamide inhibits cell growth by inducing G0/G1 arrest in the human breast cancer cell line MDA-MB-231

Abstract

BackgroundGlibenclamide (Gli) binds to the sulphonylurea receptor (SUR) that is a regulatory subunit of ATP-sensitive potassium channels (KATP channels). Binding of Gli to SUR produces the closure of KATP channels and the inhibition of their activity. This drug is widely used for treatment of type 2-diabetes and it has been signaled as antiproliferative in several tumor cell lines. In previous experiments we demonstrated the antitumoral effect of Gli in mammary tumors induced in rats. The aim of the present work was to investigate the effect of Gli on MDA-MB-231 breast cancer cell proliferation and to examine the possible pathways involved in this action.ResultsThe mRNA expression of the different subunits that compose the KATP channels was evaluated in MDA-MB-231 cells by reverse transcriptase-polymerase chain reaction. Results showed the expression of mRNA for both pore-forming isoforms Kir6.1 and Kir6.2 and for the regulatory isoform SUR2B in this cell line. Gli inhibited cell proliferation assessed by a clonogenic method in a dose dependent manner, with an increment in the population doubling time. The KATP channel opener minoxidil increased clonogenic proliferation, effect that was counteracted by Gli. When cell cycle analysis was performed by flow cytometry, Gli induced a significant cell-cycle arrest in G0/G1 phase, together with an up-regulation of p27 levels and a diminution in cyclin E expression, both evaluated by immunoblot. However, neither differentiation evaluated by neutral lipid accumulation nor apoptosis assessed by different methodologies were detected. The cytostatic, non toxic effect on cell proliferation was confirmed by removal of the drug.Combination treatment of Gli with tamoxifen or doxorubicin showed an increment in the antiproliferative effect only for doxorubicin.ConclusionsOur data clearly demonstrated a cytostatic effect of Gli in MDA-MB-231 cells that may be mediated through KATP channels, associated to the inhibition of the G1-S phase progression. In addition, an interesting observation about the effect of the combination of Gli with doxorubicin leads to future research for a potential novel role for Gli as an adjuvant in breast cancer treatment

Chronic Glibenclamide Treatment Attenuates Walker-256 Tumour Growth in Prediabetic Obese Rats

“…In the current study, Gli previous treatment was also inhibited tumour growth in rats bearing Walker-256 cancer cells. The literature shows that Gli inhibits cell growth by inducing G0/G1 arrest in the human breast cancer, cell line mda-mb-231 [28-30]. Indeed, for the first time, our findings show that chronic treatment with Gli is capable of protecting both control and prediabetic obese MSG-rats against tumour growth, even when Gli treatment was stopped one day before tumour cell grafts.…”

“…Several studies have demonstrated the effects of Gli on tumour growth arrest in different cancer types [27, 28, 37]. It has been shown that different subtypes of potassium channels are involved in normal and malignant cell proliferation [38].…”

“…Thus, Gli can bind to SUR and block the activity of numerous ABC transporters, including the multidrug transporter involved in anticancer drug resistance, which may be a promising target for anticancer therapy [7, 28]. …”

Undariopsis peterseniana Promotes Hair Growth by the Activation of Wnt/β-Catenin and ERK Pathways

“…We previously demonstrated that Ishige sinicola , a brown alga, or minoxidil, could increase the levels of cyclin E and CDK2, but decreased the level of the p27 kip1 , a CDK inhibitor in dermal papilla cells [36]. This was further supported by the observation that glibenclamide, a K ATP channel blocker, inhibited cell proliferation, which was accompanied by an increase in cell cycle arrest and the p27 kip1 level [37]. These results suggested that U. peterseniana extract increased the proliferation of dermal papilla cells through the progression of the cell cycle by the alteration of the level of cell cycle proteins.…”

Metformin use and its effect on gastric cancer in patients with type 2 diabetes: A systematic review of observational studies

“…Glibenclamide was the first second-generation sulfonylurea drug, and it functions by targeting sulfonylurea receptors (SURs). To date, a number of studies have indicated that glibenclamide can inhibit the growth of various types of cancer (51)(52)(53)(54); however, the antitumor mechanisms have not been fully elucidated. In recent years, certain studies have focused on potassium (K + ) channels, which are involved in physiological cellular functions, including insulin release, cell proliferation, and apoptosis.…”