The Bcl-2/Bcl-XL Family Inhibitor ABT-737 Sensitizes Ovarian Cancer Cells to Carboplatin

• Published in: Clinical cancer research 2007-12, Vol.13 (23), p.7191-7198
• Main Authors: WITHAM, James, VALENTI, Melanie R, DE-HAVEN-BRANDON, Alexis K, VIDOT, Susanne, ECCLES, Suzanne A, KAYE, Stan B, RICHARDSON, Alan
• Format: Article
• Language: English
• Subjects: ABT-737; Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Bcl-2; Bcl-X; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - genetics; Biological and medical sciences; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - pharmacology; Carboplatin - administration & dosage; Carboplatin - pharmacology; Cell Line, Tumor; Drug Administration Schedule; Drug Synergism; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Mice; Nitrophenols - administration & dosage; Nitrophenols - pharmacology; ovarian; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Paclitaxel - administration & dosage; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; RNA Interference; RNA, Small Interfering - genetics; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0362

Purpose: The effective treatment of ovarian cancer is hampered by the development of drug resistance, which may be mediated by members of the Bcl-2 family of apoptosis regulators. ABT-737 is a recently described inhibitor of members of this family. We investigated whether this compound could sensitize ovarian cancer cells to chemotherapeutic agents. Experimental Design: The sensitivity of ovarian cancer cell lines to ABT-737 in combination with either carboplatin or paclitaxel was tested either in vitro by assessing cell growth/survival and apoptosis or in xenograft studies. Results : As a single agent, ABT-737 inhibited the growth of eight ovarian cancer cell lines, although with relatively poor potency. However, ABT-737, but not a less active enantiomer, increased the sensitivity of several cell lines to carboplatin. The increased sensitivity to carboplatin was accompanied by a decrease in time at which apoptosis was observed when assessed according to the number of attached cells, PARP cleavage, and nucleosome formation. ABT-737 was more effective at sensitizing IGROV-1 cells when ABT-737 was administered after carboplatin. In addition, ABT-737 significantly enhanced the activity of carboplatin in one of three primary cultures derived directly from ascitic tumor cells in patients recently treated with chemotherapy. Small interfering RNA directed to Bcl-X L also increased the sensitivity of ovarian cancer cell lines to carboplatin. ABT-737 was also able to augment the inhibition of IGROV-1 tumor xenograft growth beyond that obtained with carboplatin alone. Conclusions : These data suggest that ABT-737, in combination with carboplatin, may find utility in the treatment of patients with ovarian cancer.