Abstract | OBJECTIVE: METHODS: RESULTS: RNAi screening identified at least 55 siRNAs that potentiated the growth inhibitory effects of cisplatin in SKOV3 cells. Inhibition of ATR and CHK1 resulted in the greatest modulation of cisplatin response. Drug dose response of cisplatin in the presence of siRNA validated the effects of these target genes. To show that the siRNA data could be successfully translated into potential therapeutic strategies, CHK1 was further targeted with small molecule inhibitor PD 407824 in combination with cisplatin. Results showed that treatment of SKOV3 and OVCAR3 cells with CHK1 inhibitor PD 407824 led to sensitization of ovarian cancer cells to cisplatin. CONCLUSIONS: Our data provides kinase targets that could be exploited to design better therapeutics for ovarian cancer patients. We also demonstrate the effectiveness of high-throughput RNAi screening as a tool for identifying sensitizing targets to known and established chemotherapeutic agents.
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Authors | Shilpi Arora, Kristen M Bisanz, Lourdes A Peralta, Gargi D Basu, Ashish Choudhary, Raoul Tibes, David O Azorsa |
Journal | Gynecologic oncology
(Gynecol Oncol)
Vol. 118
Issue 3
Pg. 220-7
(Sep 2010)
ISSN: 1095-6859 [Electronic] United States |
PMID | 20722101
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Copyright 2010 Elsevier Inc. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Carbazoles
- PD 407824
- Protein Kinase Inhibitors
- RNA, Small Interfering
- Protein Kinases
- CHEK1 protein, human
- Checkpoint Kinase 1
- Caspase 3
- Caspase 7
- Cisplatin
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Topics |
- Antineoplastic Agents
(pharmacology)
- Carbazoles
(pharmacology)
- Caspase 3
(metabolism)
- Caspase 7
(metabolism)
- Cell Growth Processes
(drug effects)
- Cell Line, Tumor
- Checkpoint Kinase 1
- Cisplatin
(pharmacology)
- Female
- Humans
- Ovarian Neoplasms
(drug therapy, enzymology, genetics)
- Protein Kinase Inhibitors
(pharmacology)
- Protein Kinases
(genetics, metabolism)
- RNA Interference
- RNA, Small Interfering
(genetics)
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