(1-2-bis(1-2-benzisoselenazolone-3(2h)-ketone))ethane and Prostatic-Neoplasms

Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous intracellular oxidoreductase system with antioxidant and redox regulatory roles. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In some human tumors, the thioredoxin system is found over-expressed. Because of its role in stimulating cancer cell growth and as an inhibitor of apoptosis, the Trx system offers a target for the development of drugs to treat and prevent cancer. In a previous research, we successfully synthesized a novel organoselenium compound BBSKE(1,2-[bis(1,2-Benzisoselenazolone-3(2H)-ketone)]ethane, BBSKE, PCT: CN02/00412) targeting the TrxR, and it has demonstrated the inhibitory effect on the growth of a variety of human cancer cells from various organs. In this study, we investigated the inhibitory effect of BBSKE on TrxR activity in PC-3 and DU145 human prostate cancer cell lines, and its antitumoral effect on these two cell lines. Treatment of BBSKE inhibited the TrxR activity in both of the cell lines in a dose-dependent manner and it also inhibited the proliferation of these two cell lines in a dose-dependent manner. Cell cycle analysis showed S phase arrest in both of the cell lines following 48 h exposure to BBSKE. During the S arrest, analysis of cell cycle regulatory proteins demonstrated that BBSKE increased the protein levels of cyclinA, cyclinE, and P21, but decreased the levels of cyclinB1, cyclinD1, and Cdk4. Furthermore, BBSKE decreased the protein level of Bcl-2 but increased the level of Bax, and induced apoptosis in PC-3 and DU145 human prostate cancer cell lines. These results suggest that this novel TrxR inhibitor inhibits the proliferation of prostate cancer cells via S phase arrest and apoptosis in association with the regulation of multiple molecules in the cell cycle.

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Cycle Proteins; Cell Division; Humans; Male; Organoselenium Compounds; Prostatic Neoplasms; Thioredoxin-Disulfide Reductase; Tumor Cells, Cultured

To investigate the effects of BBSKE (1,2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)]ethane), a novel organoselenium compound, on the proliferation and apoptosis of the prostate cancer cell line PC-3, and to study its effect on the growth of prostate cancer in vivo.. Prostate cancer cells of the cell line PC-3 was cultivated in media with different concentrations of BBSKE and cisplatin. The inhibition of proliferation was measured by colorimetric MTT assay. The morphologic changes were observed by fluorescence microscopy, DNA fragmentation was visualized by agarose gel electrophoresis, and the DNA degradation was determined by flow cytometry. Western blot analysis was used to identify the expression of bcl-2 and bax. The activity of caspase-3 was determined by a micro-ELISA reader. Mouse prostate cancer cells of the TRAMP-C2 line were cultured and then injected subcutaneously into 2 male C57BL/6 mice to establish the animal model. Then the 2 mice were killed to collect the cancer cells. Twenty-four mice were injected intraperitoneally with single cell suspension of TRAMP-C2 cell and then divided into 3 groups of 8 mice undergoing intraperitoneal injection for 7 days: BBSKE group (BBSKE was administered at the dosage of 25mg/kg/day), cisplatin group (cisplatin 2mg/kg/d was injected), and control group (pure solvent was injected). Three weeks after the mice were killed and the tumors were taken out to calculate the inhibition rate.. BBSKE inhibited the growth of the PC-3 cells dosage-dependently with a value of IC(50) of 17.90 micro mol/L after a 48 h exposure, higher than that in the case of cisplatin (15.00 micro mol/L). After exposure of PC-3 cells to BBSKE at the dosage of 20 micro mol/L for 48 hours the apoptosis rate was 26.32%, significantly higher than that of the control group (1.75%, P < 0.01). The expression of bcl-2 was decreased and the expression of bax remained almost unchanged along with the increase of BBSKE concentration. The activity of caspase 3 in the subgroup of BBSKE of the concentration of 5 micro mol/L remained almost unchanged, and was increased to 3.65 +/- 0.57 and 4.39 +/- 1.01 respectively in the BBSKE 10 micro mol/L and 20 micro mol/L subgroups, both significantly higher than that of the control group (both P < 0.05). In the in vivo experiment, the growth of tumor was significantly inhibited by BBSKE with an inhibition rate of 40% and the inhibition rate of the cisplatin group was 48%.. The novel organoselenium BBSKE inhibits the proliferation of PC-3 cell and promote its apoptosis, probably through downregulating the expression of bcl-2 and the activity of caspase-3. BBSKE also inhibits the growth of prostate cancer in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Caspases; Cell Division; Cell Line, Tumor; Humans; Male; Mice; Mice, Inbred C57BL; Organoselenium Compounds; Prostatic Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2