adarotene and Carcinoma

To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent and -independent pathways, regulated by MAP kinases, which likely play a protective role.

Topics: Adamantane; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma; Caspases; Cell Division; Cell Line, Tumor; Cinnamates; DNA Damage; DNA Repair; DNA, Neoplasm; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinases; Molecular Structure; Ovarian Neoplasms; Proliferating Cell Nuclear Antigen; Stress, Physiological; Transcription Factor AP-1; Tumor Suppressor Protein p53