Abstract #1857: The novel HSP90 inhibitor, PU-H71, synergizes with cisplatin and blocks invasion and migration of ovarian cell lines.

Ovarian cancer is the fifth leading cause of cancer deaths in women, with only a small fraction of cases detected at a localized, surgically curable stage. The remainder is treated with resection followed by standard platinum based chemotherapy. Acquired resistance to cisplatin is common, and presents a significant challenge to the prevention and treatment of relapse. Growth-promoting proteins and the signal transduction pathways activated during development of chemoresistance frequently depend on the Heat shock protein 90 (HSP90) chaperone for proper folding. Thus, inhibition of HSP90 presents a viable option for management of chemoresistant tumors. PU-H71 is a novel purine-scaffold class small molecule HSP90 inhibitor. We examined the effect of PU-H71, alone or in combination with cisplatin, on growth, survival and invasiveness of HeyA8 and SKOV3 ovarian cancer cell lines. Synergistic inhibition of cell growth was observed with the combination even at low concentrations of both drugs. Because peritoneal spread of ovarian cancer cells is largely responsible for clinical relapse, we examined the effect of PU-H71 on migration and invasion using fluorescently-labeled cells. Exposure of cells to PU-H71 blocked cell migration in wound-healing assays, as well as invasion through Matrigel. Inhibition of cell motility was associated with a flattened morphology, appearance of stress fibers and re-organization of actin cytoskeleton. Inhibition of cell migration was evident after a short (4 h) exposure to the drug, whereas longer exposure was required for inhibition of invasion. Our findings indicate that PU-H71 is a potent inhibitor of tumor invasion and sensitizes ovarian cells to cisplatin. These studies provide basis for future pre-clinical and clinical evaluation of PU-H71 as a suitable complement to platinum-based regimens for management of advanced ovarian cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1857.