Cisplatin ototoxicity

Cisplatin continues to be widely used to treat a variety of solid and disseminated forms of cancer; however, a major dose-limiting side effect of cisplatin is its ototoxic side effects, which can result in a lifetime of hearing impairment when given to young children. Because the ototoxic side effects of cisplatin are exacerbated by loop inhibiting diuretics such as ethacrynic acid and furosemide, extreme caution should be exercised in using these drugs in combination. Loop inhibiting drugs such as ethacrynic acid appear to potentiate the ototoxic effects of cisplatin by disrupting the blood-ear barrier thereby facilitating the uptake of cisplatin in the fluid space of the inner ear. Recent evidence suggests that three copper transporters, CTR1, ATP7A and ATP7B regulate the cellular uptake, sequestration and extrusion of cisplatin in many different cells including those of the inner ear. After entering the cytoplasm, cisplatin binds to DNA resulting in intrastrand and interstrand cross links that lead to DNA damage. Left unrepaired, DNA damage can trigger an apoptotic response that includes the upregulation of p53, an important tumor suppressor protein. Increased expression of p53 leads to the upregulation of caspase 1 and executioner caspase 3 resulting in hair cell death. Application of pifithrin-α, a small molecule that temporarily inhibits p53, blocks the increase in caspase 3 in cochlear cultures and prevents cisplatin-induced hair cell death in a dose dependent manner. The increased understanding of the mechanisms underlying cisplatin induced ototoxicity may lead to more effective methods of preventing its toxic side effects, thus allowing for more effective use of this important anticancer agent.