acetyl-aspartyl-glutamyl-valyl-aspartal and Endometrial-Neoplasms

The goal of this study was to examine the effect of ursolic acid, a pentacyclic triterpenoid compound, on growth of the endometrial cancer cell line SNG-II. We found that ursolic acid strongly inhibited the growth of SNG-II cells in a dose- and time-dependent manner. Morpholgical changes characteristic of apoptosis were observed in treated cells, such as the presence of apoptotic bodies and fragmentation of DNA into oligonucleosomal-sized fragments. We also investigated the active forms of caspase-3, -8 and -9 in ursolic acid-treated SNG-II cells. At 25 and 50 microM strength, ursolic acid induced marked increases in caspase-3 activity to approximately 5-fold that of control cells. Levels of cleaved caspase-3 increased in a time- and dose-dependent manner. Activation of caspases also led to the cleavage of target proteins, such as PARP. Ursolic acid treatment also resulted in a cleavage of poly (ADP-ribose) polymerase in a dose-dependent manner. Testing whether caspase-3 activation and DNA polymerase activity were inhibited by addition of Ac-DEDV-HCO during ursolic acid treatment showed that 50 microM Ac-DEDV-HCO inhibited caspase-3 activity in treated cells. Although DNA fragmentation was observed after ursolic acid treatment, DNA fragmentation did not occur in SNG II cells treated with both Ac-DEDV-HCO and ursolic acid. Because some researchers have suggested that mitochondrial pathways are involved in ursolic acid-induced apoptosis secondary to induction of mitochondrial cytochrome c release, we studied mitochondrial events in ursolic acid-induced apoptosis in these cell lines. After ursolic acid treatment, the anti-apoptotic Bcl-2 protein decreased and Bax expression was enhanced. Our results indicated that ursolic acid induced apoptotic processes in the endometrial cancer SNG-II cell line through mechanisms involving mitochondrial pathways and Bcl-2 family proteins.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cytochromes c; DNA; DNA Fragmentation; Endometrial Neoplasms; Female; Humans; Mitochondria; Oligopeptides; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Triterpenes; Up-Regulation; Ursolic Acid

We studied the effect of ursolic acid, a pentacyclic triterpene acid, on the growth of poorly differentiated type endometrial cancer HEC108 cells in vitro. Ursolic acid strongly inhibited the growth of HEC108 cells in a dose- and time-dependent manner. Morphological changes characteristic of apoptosis were observed in ursolic acid-treated cells, such as the presence of apoptotic bodies and fragmentation of DNA to oligonucleosomal-sized fragments. Investigation of caspase activity in ursolic acid-treated HEC108 cells showed that exposure at 50, 75 or 100 microM induced marked increases in caspase-3 activity (after 24 h) to 5.00, 11.76 or 12.75 times that of control levels, while cleaved caspase-3 levels increased in dose-dependent manner after 24 h. Activation of caspase was shown to lead to the cleavage of target proteins such as PARP. Ursolic acid treatment also resulted in a cleavage of poly(ADP-ribose) polymerase in a dose-dependent manner. Testing whether caspase-3 activation and DNA polymerase activity were inhibited by the addition of Ac-DEDV-HOC during ursolic acid treatment showed that 50 microM Ac-DEDV-HOC inhibited caspase-3 activity in treated cells. A mitochondrial pathway has been suggested to be involved in ursolic acid-induced apoptosis because the treatment induces mitochondria cytochrome c release. Experimentally, we found that anti-apoptotic Bcl-2 protein levels decreased after ursolic acid treatment, while Bax expression increased. Our results indicated that ursolic acid induced apoptotic processes in these poorly differentiated endometrial cancer cells occurs through mechanisms involving mitochondrial pathways and Bcl-2 family proteins.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptotic Protease-Activating Factor 1; bcl-2-Associated X Protein; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Tumor; Cell Proliferation; Cysteine Proteinase Inhibitors; Cytochromes c; DNA Fragmentation; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Oligopeptides; Poly(ADP-ribose) Polymerases; Proteins; Proto-Oncogene Proteins c-bcl-2; Time Factors; Triterpenes; Ursolic Acid