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

Jagjit S. Gill, Anthony John Windebank

Research output: Contribution to journalArticle

216 Citations (Scopus)

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
StatePublished - Jun 15 1998

Fingerprint

Spinal Ganglia
Cisplatin
Cell Cycle
Apoptosis
Neurons
PC12 Cells
Cyclin D1
Nerve Growth Factor
Up-Regulation
Platinum Compounds
Nerve Growth Factor Receptors
Neoplasms
Retinoblastoma Protein
Caspase Inhibitors
Nerve Growth Factors
Sensory Receptor Cells
Electron Microscopy
Cell Death
Phosphorylation
DNA

Keywords

  • Chemotherapy
  • Nerve growth factor
  • Neurotrophins
  • Platinum neurotoxicity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. / Gill, Jagjit S.; Windebank, Anthony John.

In: Journal of Clinical Investigation, Vol. 101, No. 12, 15.06.1998, p. 2842-2850.

Research output: Contribution to journalArticle

@article{540809ecd53541f48fae408d6a02de90,
title = "Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle",
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.",
keywords = "Chemotherapy, Nerve growth factor, Neurotrophins, Platinum neurotoxicity",
author = "Gill, {Jagjit S.} and Windebank, {Anthony John}",
year = "1998",
month = "6",
day = "15",
language = "English (US)",
volume = "101",
pages = "2842--2850",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",

}

TY - JOUR

T1 - Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle

AU - Gill, Jagjit S.

AU - Windebank, Anthony John

PY - 1998/6/15

Y1 - 1998/6/15

N2 - 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.

AB - 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.

KW - Chemotherapy

KW - Nerve growth factor

KW - Neurotrophins

KW - Platinum neurotoxicity

UR - http://www.scopus.com/inward/record.url?scp=0032526263&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032526263&partnerID=8YFLogxK

M3 - Article

C2 - 9637718

AN - SCOPUS:0032526263

VL - 101

SP - 2842

EP - 2850

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 12

ER -