Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle

Jagjit S. Gill, Anthony J. Windebank

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Platinum compounds induce apoptosis in malignant cells and are used extensively in the treatment of cancer. Total dose is limited by development of a sensory neuropathy. We now demonstrate that when rats are administered cisplatin (2 mg/kg i.p. for 5 d), primary sensory neurons in the dorsal root ganglion die by apoptosis. This was reproduced by exposure of dorsal root ganglion neurons and PC12 cells to cisplatin (3 μg/ml) in vitro. Apoptosis was confirmed by electron microscopy, DNA laddering, and inhibition by the caspase inhibitor z-VAD.fmk (100 μM). Cell death in vitro was preceded by upregulation of cyclin D1, cdk4, and increased phosphorylation of retinoblastoma protein; all are indicators of cell cycle advancement. The level of p16(INK4a), an endogenous inhibitor of the cyclin D1/cdk4 complex decreased. Exposure of PC12 cells and dorsal root ganglion neurons to increased levels of nerve growth factor (100 ng/ml) prevented both apoptosis and upregulation of the cell cycle markers. Cancer cells without nerve growth factor receptors (gp(140TrkA)) were not protected by the neurotrophin. This indicated that cisplatin may kill cancer cells and neurons by a similar mechanism. In postmitotic neurons, this involves an attempt to re-enter the cell cycle resulting in apoptosis which is specifically prevented by nerve growth factor.

Original languageEnglish (US)
Pages (from-to)2842-2850
Number of pages9
JournalJournal of Clinical Investigation
Volume101
Issue number12
DOIs
StatePublished - Jun 15 1998

Keywords

  • Chemotherapy
  • Nerve growth factor
  • Neurotrophins
  • Platinum neurotoxicity

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle'. Together they form a unique fingerprint.

Cite this