Gentamicin-Induced Cytotoxicity Involves Protein Kinase C Activation, Glutathione Extrusion and Malondialdehyde Production in an Immortalized Cell Line from the Organ of Corti

Abstract

The objective of the present study was to investigate the biochemical mechanisms underlying gentamicin cytotoxicity in OC-k3 cells derived from an immortalized cell line developed from the organ of Corti of transgenic mice. Administration of 50 µM gentamicin significantly reduced cell proliferation and viability, as well as initiating morphological changes associated with apoptosis. Protein kinase C (PKC) α activity was increased in gentamicin-treated cells, peaking 15 min after dosing (+138.2%). This PKCα increase was followed by a rise of glutathione (GSH) efflux and a concomitant 29% decrease in intracellular GSH levels at 30 min. PKCα-specific inhibitors blocked these cytotoxic effects. Gentamicin also increased malondialdehyde levels, while N-acetylcysteine, GSH and ascorbic acid prevented gentamicin-induced cell death. These findings suggest that gentamicin cytotoxicity involves a production of intracellular reactive oxygen species and a concomitant PKC-dependent fall of intracellular scavenging abilities (GSH), events that together drive cells to undergo apoptosis.

Otoprotective Properties of Mannitol Against Gentamicin Induced Hair Cell Loss

“…gentamicin, in contradistinction to cisplatin, has been shown to cause ototoxicity by formation of reactive oxygen species through the superoxide radical. The effects of gentamicin-induced reactive oxygen species in the organ of Corti explants are of increasing severity from the base to apex of outer hair cells (1). The sensitivity of basal turn hair cells has been linked to lower levels of glutathione as compared with levels of this antioxidant in the apex.…”

Gentamicin nephrotoxicity in animals: current knowledge and future perspectives

“…Some authors described that GM in in vitro conditions decrease proliferation of human epidermal keratinocyte, probably through inhibition of transport RNA (Tekos et al, 2003[86]). Also GM inhibits cell proliferation in the organ of Corti and cells similar to human osteoblasts (Bertolaso et al, 2003[9]). The observed differences in GM effects on various cell is probably dependent on drug concentration as well as experimental conditions.…”

Autophagy-related protein 12 associates with anti-apoptotic B cell lymphoma-2 to promote apoptosis in gentamicin-induced inner ear hair cell loss

“…In recent years, a variety of cephalosporins and quinolones have been widely used in clinics because of their longer post-antibiotic effects against Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; however, aminoglycosides are used for the treatment of severe infections from aerobic gram-negative bacillus, including meningitis, trauma, burns and respiratory tract, urinary tract, skin soft tissue, joint and gastrointestinal tract infections (29). Previous studies have reported that the GM-induced hearing loss is associated with damage of cilia and hair cells (1,30). …”

“…Aminoglycosides are renowned antibiotics primarily used in clinics for the treatment of tuberculosis, and effectively cure infections caused by aerobic gram-negative bacteria (1)(2)(3). Gentamicin (GM) is a widely-used aminoglycoside antibiotic that has attracted increasing attention recently due to its potent ototoxic side effects.…”