Cisplatin toxicity in the developing brain displays an absolute requirement for caspase-3

Abstract

Cisplatin is a member of a widely utilized class of chemotherapeutic agent that initiates DNA damage response, cell cycle arrest, and p53-dependent apoptotic cell death in concert with DNA‑platinum adduct formation. While normal programmed cell death (PCD) can occur in the developing neuroepithelium in the absence of caspase-3 within certain genetic backgrounds, we observed an absolute dependency upon this executioner caspase with respect to cisplatin-induced PCD in the developing central nervous system (CNS). We therefore examined the nature of this genotoxic injury in the CNS in vivo, in which cisplatin treatment causes widespread cellular injury consistent with hallmarks of apoptosis which are averted upon caspase-3 inhibition. Examination of cisplatin-mediated injury as a function of time revealed the presence of an alternative, delayed form of necroptosis-like cell death which manifests in Casp3^-/- neuroepithelia for several days following the normal pattern of apoptosis. Together, these findings suggest a coordinated regulation of these disparate PCD pathways in response to genotoxic stress in vivo and highlight the unique and critical role which caspase-3 plays among executioner caspases in coordinating apoptotic versus necroptotic responsiveness of the developing CNS to genotoxic injury.

Keywords: Apoptosis; Caspases; Cisplatin; Neural stem cells.