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Review
. 2013;18(10):1118-25.
doi: 10.1634/theoncologist.2013-0177. Epub 2013 Sep 16.

Effects of sulfonylureas on tumor growth: a review of the literature

Giulia Pasello  1 , Loredana Urso, Pierfranco Conte, Adolfo Favaretto
Affiliations
Review

Effects of sulfonylureas on tumor growth: a review of the literature

Giulia Pasello et al. Oncologist. 2013.

Abstract

Type 2 diabetes mellitus patients are at higher cancer risk, probably because of hyperinsulinemia and insulin growth factor 1 pathway activation. The effects of antidiabetic drugs on cancer risk have been described and discussed in several studies suggesting opposite effects of the biguanide metformin and sulfonylureas on cancer incidence and mortality. The anticancer mechanisms of metformin have been clarified, and some clinical studies, particularly in breast cancer patients, have been published or are currently ongoing; however, data about the effects of sulfonylureas on cancer growth are less consistent. The aims of this work are to review preclinical evidence of second-generation sulfonylureas effects on tumor growth, to clarify the potential mechanisms of action, and to identify possible metabolic targets for patient selection. Most evidence is on the adenosine triphosphate-sensitive potassium channels inhibitor glibenclamide, which interacts with reactive oxygen species production thus inducing cancer cell death. Among diarylsulfonylureas, next-generation DW2282 derivatives are particularly promising because of the proapoptotic activity in multidrug-resistant cells.

Keywords: Anticancer agents; Apoptosis; Glibenclamide; Sulfonylurea compounds.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
Insulin and IGF pathway. Insulin and IGF bind to insulin receptors and IGF receptors, activating insulin receptor substrates and, subsequently, mitogen-activated protein kinase and PI3K-Akt-mTOR pathways. These signals lead to cell survival and proliferation. Abbreviations: IGF, insulin growth factor; IR, insulin receptor; IRS, insulin receptor substrates; mTOR, mammalian target or rapamycin; PI3K, phosphoinositide 3 kinase; SOS, son of sevenless; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase/ERK kinase; ERK, extracellular signal-regulated kinases; TSC, tuberous sclerosis complex; S6K, S6 protein kinase.
Figure 2.
Figure 2.
Glibenclamide-dependent secretion of insulin in pancreatic β cells. Physiologically, glucose influx into pancreatic β cell induces ATP synthesis through glycolysis and mitochondrial respiration with subsequent K+ channel closure. In type 2 diabetes mellitus patients, glibenclamide directly closes ATP-sensitive K+ channels, reducing membrane potential and inducing calcium influx, which in turn stimulates insulin secretion. Abbreviations: ATP, adenosine triphosphate; Ca2+, calcium ion; K+, potassium ion.
Figure 3.
Figure 3.
Proposed model for antitumor activity of glibenclamide. Glibenclamide increases NADPH oxidase and mitochondrial respiratory chain ROS production followed by release of proapoptotic factors and caspase activation. Membrane depolarization by glibenclamide and TRAIL induces ER stress-mediated apoptosis. Glibenclamide sensitizes tumor cells to TRAIL-dependent apoptosis through membrane depolarization and ROS production. Abbreviations: Cas, caspase; ER, endoplasmic reticulum; K+, potassium ion; rc, respiratory chain; ROS, reactive oxygen species; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand.
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