Research Project
10163157
Cisplatin is a widely used chemotherapeutic agent for the treatment of a variety of human cancers. However, the therapeutic benefits of this drug are compromised by dose limiting side effects such as ototoxicity, nephrotoxicity and neurotoxicity. The incidence of cisplatin-induced hearing deficits, assessed by audiometric studies, range from 75-100%. In the pediatric population, where cisplatin is used to treat neuroblastomas and central nervous system malignancies, loss of hearing could hamper speech, cognition and social development of the child. Other drugs, such as carboplatin and oxaliplatin, have emerged as alternatives to cisplatin, but their usefulness is limited to a few cancers and they produce consistent neuropathies. Cisplatin is shown to be more effective than carboplatin in treating non-small-cell lung cancer even though the side effects of the two drugs appear equivalent. Thus, cisplatin still retains its importance as a component of the chemotherapeutic regimen for various cancers. While the mechanism of chemotherapeutic efficacy of cisplatin appears to be DNA alkylation, the generation of reactive oxygen species (ROS) via NOX3 NADPH oxidase appears critical for mediating cisplatin ototoxicity and nephrotoxicity. This has stimulated interest for using antioxidants as otoprotectants. A limitation of this approach, however, is that thiol-containing antioxidants could interfere with cisplatin antitumor efficacy. We have recently shown that signal transducer and activator of transcription 1 (STAT1) couples ROS (from cisplatin) to the inflammatory cascade, which exacerbates hearing loss. We also shown that knockdown of STAT1 (by siRNAs) protects against cisplatin-induced hearing loss. Moreover, our preliminary data show that epigallocatechin gallate (EGCG), the most abundant catechin in green tea and an inhibitor of STAT1 protects against cisplatin ototoxicity. Interestingly, EGCG also activates STAT3, a transcription factor linked to cell survival. These dual mechanisms of otoprotection by EGCG would be explored in more detail in this grant proposal. An added advantage of EGCG is that it possesses intrinsic anticancer properties and does not interfere with cisplatin chemotherapeutic efficacy in initial studies. The goals of this proposal are to determine the efficacy of oral EGCG against cisplatin ototoxicity and nephrotoxicity in rats (Specific aims 1). The mechanisms underlying the protective action of EGCG against cisplatin ototoxicity, focusing on the STAT1 and STAT3 pathways and gene expression analysis, will be examined in Specific aim 2. Specific aim 3 will determine potential antitumor interference by EGCG against different tumor cells in xenograft mouse models. The results provided in this study would provide a better understanding of the utility of EGCG for the treatment of cisplatin oto- and nephrotoxicity and could support its therapeutic use in cancer patients. Furthermore, this study should expand our knowledge concerning the importance of STAT1/STAT3 balance in hair cell survival.
