An integrated view of cisplatin-induced nephrotoxicity and ototoxicity

Abstract

Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.

Keywords: Cisplatin; Intracellular mechanisms; Nephrotoxicity; Ototoxicity.

Fig. 1

(A) Platinum compounds. (B) In vitro cisplatin nephrotoxicity assay results. Mouse kidney proximal tubule KPT11 cells were treated with each platinum compound (all purchased from Sigma) for 2 days before cellular viability was measured by MTT assay.

Fig. 2

Apoptosis signaling pathways in cisplatin nephrotoxicity. In the extrinsic pathway, binding of TNF-α to TNF receptors activates caspase 8, which in turn triggers caspase 3, leading to apoptosis. ER stress induced by cisplatin activates caspase 12 also leads to apoptosis. DNA damage triggers p53, which in turn activates PUMA-α and PIDD. PUMA-α is a pro-apoptotic Bcl-2 family protein which inhibits anti-apoptotic Bcl-2. PIDD activation leads to release of apoptosis-inducing factor (AIF) from mitochondria. This intrinsic pathway leads to release of mitochondrial cytochrome c that sequentially activates caspase 9, 3, 6 and 7, resulting in apoptosis.

Fig. 3

(A) A cross-section of the right-side of the human head, showing the peripheral auditory (external and middle ear, as well as the cochlea [inner ear]) system, and the semicircular canals of the peripheral vestibular system (adapted from an image by British Columbia Children’s Hospital, image is not to scale). (B) A cross-section of the cochlear duct shown in (A) as a thick line. The cochlear duct is divided into three compartments, two of which contain perilymph, and an inner compartment, the scala media, containing endolymph. Systemic cisplatin could cross the BLB via a trans-strial trafficking route from strial capillaries, across the stria vascularis in endolymph (1) prior to entering hair cells across their apical membranes (2). Alternatively, cisplatin could traverse the BLB into perilymph and pass through the basilar membrane into extracellular fluids within the organ of Corti and enter hair cells across their basolateral membranes. S, stria vascularis; adapted from Brock et al. (2012), image is not to scale.

Fig. 4

A schematic pathway for one mechanisms of cisplatin-induced ototoxicity involves TRPV1 activation by cisplatin leads to NOX3-dependent generation of ROS to trigger STAT1 activation. STAT1 promotes an intracellular inflammatory response and p53 activation, resulting in cell death, adapted from Mukherjea et al. (2011a, .