Developing a Nutraceutical Product against Ototoxicity

PROJECT SUMMARYDespite recent advances in cancer therapiesplatinum based drugs are still widely used for the treatment of solid tumorsA primary example is cisplatinwhich is frequently used to treat lungbladdertesticularand cervical cancersHoweverlimitations of this therapy include the development of drug resistance in cancer cells as well as severe side effectssuch as nephrotoxicity and neurotoxicityOne major type of peripheral sensory neurotoxicity is ototoxicityor drug induced damage to the inner earand cisplatin is the most ototoxic compound that can cause bilateral and irreversible hearing lossWhile DNA damage by cisplatin is the major cytotoxic mechanism in cancer cellscisplatin induced ototoxicity appears to result from toxic levels of reactive oxygen species and other signaling dysregulation within various cellular compartmentsA variety of agents have been tested against cisplatin induced ototoxicitymainly based on their antioxidant propertiesHowevermany of them show limited efficaciesand also interfere with the therapeutic effect of cisplatinIn our preliminary studieswe have found that tetrandrineTETa compound isolated from the herb Stephanai tetrandracan protect against noise induced hearing lossPrevious studies have also revealed that TET can act synergistically with other cancer treatments in several important aspectsincreasing tumor cell cytotoxicityenhancing radiosensitizationreducing multidrug resistanceand inhibiting angiogenesisAt the molecular levelTET can block calcium channelsdownregulate multiple drug resistant proteinsand modulate signaling pathways important for the inflammatory responseBased on these findingswe propose a proof of concept project to test whether TET can synergistically work with cisplatin to induce cancer cell death andat the same timeprevent cisplatininduced ototoxicityBecause lung cancer is the leading cause of cancer related death globallyand because cisplatin is widely used to treat this diseasewe will be focusing on lung cancer cell lines for this studyWe will first study the cytotoxic effects of TET and cisplatin in three lung cancer cell lines and one cochlear cell lineand determine whether TET and cisplatin have synergistic effects when used in combination against these cancer cells while TET has no ototoxic effects on the cochlear cell lineAimWe will then determine whether the TET can prevent cisplatin induced ototoxicity in vivo while preserving or enhancing anti tumor efficacyAimOur project goal is to develop a new product to combine with cisplatin against lung cancerThis project will generate data important for developing new approaches to reduce cisplatin induced ototoxicity Public Health Relevance Narrative Platinum based drugs such as cisplatin are still widely used to treat solid tumors with limited efficacies and serious side effectsThis project has the potential to reduce ototoxicity and increase the efficacy of cisplatin by developing a new solution