Screening the Sigma LOPAC®1280 library of compounds for protective effects against cisplatin-induced oto- and nephrotoxicity

Dose-limiting toxicities for cisplatin administration, including
ototoxicity and nephrotoxicity, impact the clinical utility of this
effective chemotherapy agent and lead to lifelong complications,
particularly in pediatric cancer survivors. Using a two-pronged drug
screen employing the zebrafish lateral line as an in vivo readout for
ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280
compounds and identified 22 that were both oto- and
nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino
acid active in the dopamine pathway, were further investigated. Dopamine
and L-mimosine protected the hair cells in the zebrafish otic
vesicle from cisplatin-induced damage and preserved zebrafish larval
glomerular filtration. Importantly, these compounds did not abrogate the
cytotoxic effects of cisplatin on human cancer cells. This study provides
insights into the mechanisms underlying cisplatin-induced oto- and
nephrotoxicity and compelling preclinical evidence for the potential
utility of dopamine and L-mimosine in the safer administration of
cisplatin.