Protective Effect of Metformin Against Cisplatin-Induced Ototoxicity in an Auditory Cell Line

Abstract

Metformin, an antidiabetic drug with potent anticancer activity, is known to prevent oxidative stress-induced cell death in several cell types through a mechanism dependent on the mitochondria. In the present study, we investigated the influence of metformin on cisplatin ototoxicity in an auditory cell line. Cell viability was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (Sigma, St. Louis, MO, USA) cell proliferation assay. Oxidative stress and apoptosis were assessed by flow cytometry analysis, Hoechst 33258 staining, reactive oxygen species (ROS) measurement, and western blotting. Intracellular calcium concentration changes were detected using calcium imaging. Pretreatment with 1 mM metformin prior to the application of 20 μM cisplatin significantly decreased the frequency of late apoptosis in HEI-OC1 cells and also significantly attenuated the cisplatin-induced increase in ROS. In addition, metformin inhibited the activation of caspase-3 and levels of poly-ADP-ribose polymerase (PARP). Pretreatment with metformin prevented the cisplatin-induced elevation in intracellular calcium concentrations. We propose that metformin protects against cisplatin-induced ototoxicity by inhibiting the increase in intracellular calcium levels, preventing apoptosis, and limiting ROS production.

Effect of Remote Ischemic Preconditioning on Systemic Toxicity and Ototoxicity Induced by Cisplatin in Rats: Role of TNF-α and Nitric Oxide

“…Other agents interfere only with the ototoxicity of cisplatin, including Gingko biloba [42], ebselen (a synthetic compound with an activity similar to that of glutathione peroxidase) [43], and amifostine [24]. Other protective compounds, whose antineoplastic effects have not been evaluated, include metformin [3] and silymarin, a lipophilic extract derived from the plant Silybum marianum [23]. A suggestion made by some studies is the application of protective agents such as D -methionine and N -acetylcysteine directly to the eardrum or via the round window to abolish the interference with the systemic toxicity induced by cisplatin [13].…”

“…This kind of toxicity can interfere with drug treatment in many patients by necessitating decreases in the dosage, frequency, and duration of chemotherapy [2]. There is no cure or preventive treatment of ototoxicity in these patients [3]. This effect was first described by Rossof and has been widely studied since then [4].…”

“…An increase in the levels of inducible nitric oxide synthase (iNOS) and nuclear factor-κB has also been observed [13,14]. Some compounds protect against the ototoxicity induced by cisplatin, including melatonin [15], vitamin E [16], N -acetylcysteine [17], allopurinol-ebselen [18], D -methionine [19], Ginkgo biloba [20,21], trolox [22], metformin [3], silymarin [23], and amifostine [24]. …”

Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2

“…Metformin has been demonstrated to act synergistically with DDP to decrease tumor size and inhibit angiogenesis in mice, indicating that it could bea reasonable candidate for combination with DDP-dependent therapy (3). However, a previous study found that metformin antagonizes the DDP-dependent apoptotic effect by suppressing oxidative stress and inhibiting the caspase-dependent activation of apoptosis in certain cancer cells (14). The present study examined the combination of metformin and DDP as a novel treatment for ovarian cancer.…”

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

“…Jung et al [2011] observed that metformin protects an auditory cell line against gentamicin-induced apoptosis. Recently, Chang et al [2014] showed that metformin had a protective effect against cisplatin-induced ototoxicity in an auditory cell line. These studies did not consider HCs or SGNs from cochlear tissue.…”