Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity

Bapurao Surnar, Nagesh Kolishetti, Uttara Basu, Anis Ahmad, Erik Goka, Brian Marples, David Kolb, Marc E. Lippman, Shanta Dhar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6500-6513
Number of pages14
JournalBiochemistry
Volume57
Issue number46
DOIs
StatePublished - Nov 20 2018

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Cisplatin
Prodrugs
Nausea
Drug Approval
DNA
United States Food and Drug Administration
Urinary Bladder Neoplasms
DNA Repair
Ovarian Neoplasms
Energy Metabolism
Aspirin
DNA Damage
Dosimetry
Toxicity
Neoplasms
Guinea Pigs
Repair
Therapeutics
Radiation
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

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Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity. / Surnar, Bapurao; Kolishetti, Nagesh; Basu, Uttara; Ahmad, Anis; Goka, Erik; Marples, Brian; Kolb, David; Lippman, Marc E.; Dhar, Shanta.

In: Biochemistry, Vol. 57, No. 46, 20.11.2018, p. 6500-6513.

Research output: Contribution to journalArticle

Surnar, B, Kolishetti, N, Basu, U, Ahmad, A, Goka, E, Marples, B, Kolb, D, Lippman, ME & Dhar, S 2018, 'Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity', Biochemistry, vol. 57, no. 46, pp. 6500-6513. https://doi.org/10.1021/acs.biochem.8b00712
Surnar, Bapurao ; Kolishetti, Nagesh ; Basu, Uttara ; Ahmad, Anis ; Goka, Erik ; Marples, Brian ; Kolb, David ; Lippman, Marc E. ; Dhar, Shanta. / Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity. In: Biochemistry. 2018 ; Vol. 57, No. 46. pp. 6500-6513.
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