Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity

Abstract

Cisplatin is a major chemotherapeutic that continues to have a significant impact in the treatment of more than 50% of all cancers. Since its Food and Drug Administration approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity-and nausea-related side effects, but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin-A, a prodrug of cisplatin and aspirin, using preclinical mouse-and guinea pig-based models and demonstrated its efficacy with reduced ototoxicity. In addition, in vitro studies documented that when Platin-A is used in combination with a clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bioenergetic profiles, producing multiple modes of DNA damage, and delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin-A, highlighting its superior efficacy with reduced toxicity.

The protective effect of aspirin-induced temporary threshold shift in an animal model of cisplatin-related ototoxicity

“…Salicylate signi cantly attenuated the cisplatin-induced threshold shift from approximately 20 dB to 5dB at 10 days post-treatment. Similar results were presented by Minami et al [16] and Surnar et al [19]. However, in a phase 2, double-blind, randomized controlled trial aspirin failed to protect from cisplatin ototoxicity [15].…”

“…Continuous aspirin administration at high doses induces for itself hearing loss and tinnitus [17,18]. However, its effect is reversible [14,16,19]. In humans receiving high doses of 4g daily, temporary threshold shift (TTS) of 10-40dB develops and persists throughout the period of drug administration.…”

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

“…Both ENG-L06E and ENGA-L08E were more effective against UWB1.289 cells, by means of exerting significantly higher cytostatic and cytotoxic activity, which are known to be Breast cancer type 1 (BRCA1)-null (mutated, lack wild-type BRCA1 gene), in comparison to the other tested cells bearing either the BRCA1 wild type (w.t) or where at BRAC1 is restored (UWB1.289 + BRCA1 cells). Finally, both ENG-L06E and ENGA-L08E were fairly effective against OVCAR-5 and SK-OV-3 cells (both of which exert low sensitivity to the alkylator cisplatin) as well as OVCAR-3 cells, which are (i) resistant to the aniline mustard alkylator melphalan, (ii) not sensitive to cisplatin and neither to Adriamycin [13][14][15][16] (Table 1). The analytical results of the inhibitory effects of ENGA-L06E and ENGA-L08E on ERK1/2 and AKT1/2 phosphorylation, in all studied cancer cell lines, and the corresponding kinetics according to the Michaelis Menten model are illustrated in Figures 1 and 2, as well as in Tables A1 and A2.…”

<p>Inhibition of TRIM32 Induced by miR-519d Increases the Sensitivity of Colorectal Cancer Cells to Cisplatin</p>

“…24,25 However, high-dose treatment of cisplatin causes severe side effects, including neurotoxicity, nephrotoxicity, gastrointestinal reactions and myelosuppression. 26,27 Therefore, reducing the dosage of cisplatin and increasing the sensitivity of CRC cells to cisplatin is important to improve the chemotherapy effect and patient compliance. Dysregulation of miRNAs usually induces chemoresistance in various cancers including CRC.…”