The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

Abstract

Background and purpose: Ototoxicity is a known adverse effect of cisplatin (CDDP). Since apoptosis is involved in the development of some pathological conditions associated with the administration of anticancer drugs, we examined, using immunohistochemical and electrophysiological techniques, the apoptotic changes in the cochlea of Sprague-Dawley (SD) rats after an injection of CDDP (5 mgkg -1 body weight). Experimental approach: Luciferase assays were used to determine the different caspase activities and ATP levels in protein extracts of whole cochleae. The expression of several apoptotic-related proteins was measured by means of Western blotting. These analyses were performed 2, 7 and 30 days after the CDDP injection. The auditory brain stem response was obtained before and at the different times after the injection of CDDP, before the animals were killed. Key results: CDDP significantly increased the levels of caspase-3/7 activity and active caspase-3 protein expression and caspase-3 immunofluorescence staining, caspase-9 activity, and Bax protein expression but decreased Bcl-2 protein expression within the rat cochleae. Threshold shifts were significantly elevated 2 days after CDDP treatment. Conclusions and implications: These findings support the hypothesis that cisplatin-related apoptosis evokes an intrinsic pathway of pro-apoptotic signalling within the rat cochleae. Thus, selective inhibition of the sequence of events involved in the intrinsic apoptotic pathway could provide a strategy to minimize cisplatin-induced ototoxicity.

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

“…Mechanisms of cisplatin-induced ototoxicity have been well established, and the role of calcium is paramount in this process. [4][5][6]10 We hypothesized that preventing calcium influx through targeted inhibition of OHC L-type calcium channels will provide otoprotection from the apoptosis-induced effects of cisplatin. Our results are consistent with this hypothesis, and diltiazem-treated ears showed statistically significant reduction in ABR threshold versus control ears.…”

“…[1][2][3][4] Ototoxicity caused by cisplatin has effects on a number of inner ear structures, including the stria vascularis, supporting cells, spiral ganglion cells, and outer hair cells (OHCs). 2,5,6 However, the OHCs appear to be the most susceptible to damage. There is evidence that the mechanism of ototoxicity is related to formation of reactive oxygen species that damage OHCs of the cochlea and trigger apoptosis.…”

“…There is evidence that the mechanism of ototoxicity is related to formation of reactive oxygen species that damage OHCs of the cochlea and trigger apoptosis. [5][6][7] Research has explored otoprotective compounds that work by interfering with this reactive oxygen species pathway, 8,9 yet otoprotective agents have not translated to clinical practice.…”

“…5,10 Apoptosis is a dynamic event that requires coordination of many enzymatic events that ultimately lead to activation of degradative enzymes. A number of enzymes are activated during apoptosis, such as caspases 6 and calpains, 11 which are calcium-activated proteases. Thus, a major contributor to apoptosis is calcium influx.…”

A Systems Biology Analysis of Apoptosome Formation and Apoptosis Execution Supports Allosteric Procaspase-9 Activation

“…Our study may therefore direct future research to decipher one of the most fundamental processes in apoptosis signal transduction. A deeper understanding of the mechanisms of this process may also assist in directing drug design and intervention strategies for human pathologies that are associated with excessive or unwanted caspase-9-dependent apoptosis, including acute settings such as stroke, but also neurodegenerative diseases, or ototoxicity during platinum drug-based chemotherapy (61)(62)(63)(64). Due to the strongly overlapping substrate specificities in the caspase family (65), identifying highly specific inhibitors of caspase-9 may have no prospect of success.…”