Ototoxic Effects of Bound and Unbound Cisplatin

Cisplatin is a potent antitumor drug used in ~40% of cancer chemotherapy regimens together with other platinum-based drugs. However, multiple unwanted toxic effects such as neurotoxicity, nephrotoxicity, and ototoxicity, limit its usage and dosage. Cisplatin ototoxicity (CO) contributes to ~100-300 thousand new hearing impairment cases annually among the cancer patients in the US. CO is related to the generation of reactive oxygen species (ROS), causing cochlear damage, particularly the loss of outer hair cells (OHCs). To date, no effective clinical treatment for CO has been approved. Recently, our group have reported a promising candidate, honokiol, which can both protect hearing and potentiate the antitumor effect of cisplatin during chemotherapy. Honokiol works through the activation of sirtuins, the critical regulators of the anti-ROS system in the cells. This mechanism suggests that CO directly damage OHCs, possibly through direct uptake. However, no decisive evidence shows the presence of cisplatin in the OHCs. Instead, a recent publication shows that cisplatin mainly accumulates in the stria vascularis (SV) after chemotherapy. This result suggests an indirect damage to the OHCs secondary to the damage of SV. In addition, cisplatin binds to proteins and DNA, and the unbound cisplatin is thought to be the active form. Whether the potential differences of the bound and unbound cisplatin play a role in this discrepancy is also unclear. Understanding the mechanism and metabolism of cisplatin is particularly important for clinical trials involving honokiol. X-ray fluorescence microscopy (XFM), a state-of-the-art technique which can show the presence of elements in high resolution (nanometer) and sensitivity (femtogram/cm2) is a perfect tool for this purpose. In this study, we would like to determine the distribution of cisplatin in the cochlea and the roles of bound and unbound cisplatin in CO using XFM. Samples from various tissues/organs at different stages in chemotherapy will be collected. From these samples, the distribution of cisplatin in the cochlea will be determined. The concentration of bound and unbound cisplatin in the cochlea will be estimated through comparisons with other tissues, and their potentially different functions will be evaluated. This project is of great clinical significance and lays the groundwork for human tests using honokiol for hearing protection in chemotherapy.