Therapeutic Potential of the Poly(ADP-ribose) Polymerase Inhibitor Rucaparib for the Treatment of Sporadic Human Ovarian Cancer
| Autor: | Meenal Chalukya, Boris Winterhoff, Siân Jones, Nitin Udar, Teodora Kolarova, Fritz Jänicke, Gerrit Los, Dennis J. Slamon, Sugandha Dandekar, Gottfried E. Konecny, Hong Mei Rong, Victor E. Velculescu, Christine Eulenburg, Judy Dering, Maike Ihnen, Natarajan Venkatesan, Alexandra Meuter, Kanthinh Manivong, Charles Ginther, Jing Wei Qi, Lee Anderson |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Indoles endocrine system diseases Ubiquitin-Protein Ligases Apoptosis DNA Fragmentation Poly(ADP-ribose) Polymerase Inhibitors Biology Poly (ADP-Ribose) Polymerase Inhibitor Article Histones chemistry.chemical_compound Cell Line Tumor medicine Humans Doxorubicin Rucaparib BRCA2 Protein Ovarian Neoplasms Drug Synergism medicine.disease Gemcitabine Carboplatin Oncology chemistry Mutation PARP inhibitor Cancer research Female Topotecan Poly(ADP-ribose) Polymerases Ovarian cancer medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 12:1002-1015 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-12-0813 |
| Popis: | Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. Mol Cancer Ther; 12(6); 1002–15. ©2013 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|