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.
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Authors | Haiying Cheng, Zhenfeng Zhang, Alain Borczuk, Charles A Powell, Adayabalam S Balajee, Howard B Lieberman, Balazs Halmos |
Journal | Carcinogenesis
(Carcinogenesis)
Vol. 34
Issue 4
Pg. 739-49
(Apr 2013)
ISSN: 1460-2180 [Electronic] England |
PMID | 23275151
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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