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PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells.

Abstract
Platinum compounds are the foundation of chemotherapy regimens for non-small cell lung cancer (NSCLC) despite poor response rates and limited response duration. It has been reported that tumor expression of excision repair cross-complementation group 1 (ERCC1), a key component in nucleotide excision repair, may correlate with clinical response to platinum agents. We found that most primary lung tumor specimens demonstrated a stronger protein expression of poly (adenosine diphosphate ribose) polymerases 1 (PARP1) than their normal counterparts. Therefore, we hypothesized that combining PARP inhibition with platinum compounds may be an approach to improve platinum-based therapy for NSCLC. Drug combination experiments revealed that two distinct PARP inhibitors, olaparib and veliparib, not only potentiated the cell killing by cisplatin but also conferred cytotoxicity as a single agent specifically in ERCC1-low HCC827 and PC9 but not in ERCC1-high A549 and H157 lung cancer cells. Moreover, small interfering RNA knockdown of ERCC1 in A549 and H157 cells increased their sensitivities to both cisplatin and olaparib in a synergistic manner in our model. Furthermore, mechanistic studies indicated that combined PARP inhibitor and cisplatin could lead to sustained DNA double-strand breaks, prolonged G2/M cell cycle arrest with distinct activation of checkpoint kinase 1 signaling and more pronounced apoptosis preferentially in lung cancer cells with low ERCC1 expression. Collectively, these data suggest that there is a synergistic relationship between PARP inhibition and low ERCC1 expression in NSCLC that could be exploited for novel therapeutic approaches in lung cancer therapy based on tumor ERCC1 expression.
AuthorsHaiying Cheng, Zhenfeng Zhang, Alain Borczuk, Charles A Powell, Adayabalam S Balajee, Howard B Lieberman, Balazs Halmos
JournalCarcinogenesis (Carcinogenesis) Vol. 34 Issue 4 Pg. 739-49 (Apr 2013) ISSN: 1460-2180 [Electronic] England
PMID23275151 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzimidazoles
  • DNA-Binding Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RNA, Small Interfering
  • veliparib
  • Poly(ADP-ribose) Polymerases
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • ERCC1 protein, human
  • Endonucleases
  • Cisplatin
  • olaparib
Topics
  • Antineoplastic Agents (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis (drug effects)
  • Benzimidazoles (pharmacology)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Cisplatin (pharmacology)
  • DNA Breaks, Double-Stranded (drug effects)
  • DNA-Binding Proteins (biosynthesis, genetics)
  • Drug Synergism
  • Endonucleases (biosynthesis, genetics)
  • G2 Phase Cell Cycle Checkpoints (drug effects)
  • Humans
  • Lung Neoplasms (drug therapy, genetics, metabolism)
  • Phthalazines (pharmacology)
  • Piperazines (pharmacology)
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases (biosynthesis)
  • Protein Kinases (metabolism)
  • RNA Interference
  • RNA, Small Interfering

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