Cisplatin resistance associated with PARP hyperactivation Academic Article uri icon

Overview

MeSH Major

  • Antineoplastic Agents
  • Carcinoma, Non-Small-Cell Lung
  • Cisplatin
  • Drug Resistance, Neoplasm
  • Lung Neoplasms
  • Poly(ADP-ribose) Polymerase Inhibitors

abstract

  • Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis.

publication date

  • April 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-12-3000

PubMed ID

  • 23554447

Additional Document Info

start page

  • 2271

end page

  • 80

volume

  • 73

number

  • 7