UCN-01 in ovary cancer cells: Effective as a single agent and in combination with cis-diamminedichloroplatinum(II) independent of p53 status Journal Article

Authors: Husain, A.; Yan, X. J.; Rosales, N.; Aghajanian, C.; Schwartz, G. K.; Spriggs, D. R.
Article Title: UCN-01 in ovary cancer cells: Effective as a single agent and in combination with cis-diamminedichloroplatinum(II) independent of p53 status
Abstract: Our goal was to determine the cytotoxicity of 7-OH-hydroxystaurosporine (UCN-01) as a single agent and in combination with cis- diamminedichloroplatinum(II) (CDDP) in a panel of ovarian carcinoma cells. We sought to examine the role of p53 gene function and alterations in cell cycle progression or other mechanisms of action of UCN-01 including perturbation of the apoptosis pathway mediated by NF-κB and Bcl-2/Bax. Cytotoxicity was determined from dose-response curves established by the Alamar blue vital dye indicator assay. Restoration of wild-type p53 in a p53 null cell line, SKOV 3, was achieved by transfection of a p53 expression vector. Cell cycle distribution was measured by fluorescence-activated cell sorting analysis of ethidium bromide-stained nuclei. Apoptosis was measured by quantitative fluorescence microscopy. NF-κB DNA binding activity was measured by electrophoretic mobility shift assay. Bcl-2 and Bax levels were determined by Western immunoblotting. UCN-01 was effective as a cytotoxic agent alone and in combination with CDDP in all cell lines studied, regardless of p53 status. The degree of sensitization to CDDP conferred by UCN-01, however, was found to correlate with p55 gene status. p53 wild-type cells seem to be more sensitive to the cytotoxic effects of the combination of UCN-01 + CDDP than the p53 mutant cells. This was confirmed in cells in which p53 wild-type function was restored by transfection of p55 cDNA, but these cells are also significantly more sensitive to CDDP alone. The effects of UCN-01 on cell cycle progression also appear to be p53 dependent but may not be the primary mechanism of action. The rate of apoptosis is increased 4-fold in UCN-01 + CDDP-treated cells compared to either agent alone. UCN-01 does not effect NF- κB DNA binding activity or Bcl-2 and Bax levels. UCN-01 enhances CDDP cytotoxicity and apoptosis in ovary cancer cells. This occurs regardless of p53 status, but wild-type p53 seems to increase the degree of sensitization.
Keywords: controlled study; human cell; cisplatin; cancer combination chemotherapy; antineoplastic agents; ovarian neoplasms; cell survival; cell cycle; apoptosis; ovary cancer; immunoglobulin enhancer binding protein; cancer cell culture; tumor cells, cultured; transfection; protein p53; time factors; drug synergism; recombinant proteins; tumor suppressor protein p53; drug cytotoxicity; alkaloids; mutagenesis; complementary dna; genes, p53; staurosporine; 7 hydroxystaurosporine; humans; human; female; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 3
Issue: 11
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 1997-11-01
Start Page: 2089
End Page: 2097
Language: English
PUBMED: 9815601
PROVIDER: scopus
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus