Synergistic induction of apoptosis by methylseleninic acid and cisplatin, the role of ROS-ERK/AKT-p53 pathway.

Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop chemosensitizing agents to cisplatin. In the present study, we demonstrated the strategy to use methylseleninic acid (MeSe) as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of MeSe and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cell and normal cell. By inducing intracellular oxidative stress, MeSe potentiated cisplatin-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathway. Down-regulation of phosphorylated AKT and ERK also played important roles in the synergistic effects of MeSe and cisplatin. Our results suggested that the strategy to apply MeSe as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by targeting the intracellular redox system. MeSe might be a candidate for clinical application as a chemosensitizer to cisplatin-based therapy for cancer treatments, especially for hepatocellular carcinoma.

Sialic acid surface decoration enhances cellular uptake and apoptosis-inducing activity of selenium nanoparticles.

A simple method for fabrication of sialic acid surface-decorated selenium nanoparticles (SA-Se-NPs) with enhanced cancer-targeting and cell-penetrating abilities has been demonstrated in the present study. Monodisperse and homogeneous spherical SA-Se-NPs with striking stability were prepared under the optimized conditions. SA surface decoration significantly increased the cellular uptake and cytotoxicity of Se-NPs in HeLa human cervical carcinoma cells. Treatments of SA-Se-NPs induced dose-dependent apoptosis in HeLa cells, as evidenced by increase in sub-G1 cell populations, nuclear condensation and formation of apoptotic bodies. Further investigation on molecular mechanisms reveals that SA-Se-NPs triggered cancer cell apoptosis through activation of caspase-3 and subsequent cleavage of PARP.

[Artesunate suppresses human endometrial carcinoma RL95-2 cell proliferation by inducing cell apoptosis].

OBJECTIVE: To investigate the inhibitory effect of artesunate on human endometrial carcinoma RL95-2 cell line proliferation in vitro and the possible mechanisms. METHODS: The inhibitory effect of artesunate on the cell proliferation was assessed with MTT assay. Transmission electron miscrosopy was used to observe the morphological change of the cells after the treatment. Flow cytometry was performed to examine the changes in the cell cycle, reactive oxygen species (ROS) levels (with DCFH-DA labeling) and mitochondrial membrane potential (rhodamine123 staining), and caspase-3 activity was detected by immunohistochemistry. RESULTS: Artesunate inhibited the proliferation of RL95-2 cells with an IC(50) of 26.29 microg/ml. Transmission electron microscopy revealed early apoptotic changes of the cells with obvious chromatin fragmentation. The cell cycle arrest at G(0)/G(1) phase was observed by flow cytometry, and immunohistochemistry demonstrated caspase-3 positivity in cytoplasm. ROS generation in the cells increased obviously after treatment with artesunate for 72 h, which also resulted in lowered mitochondrial membrane potential. CONCLUSION: Artesunate suppressed the proliferation of RL95-2 cells in vitro possibly by inducing cell apoptosis.

[Effects of exogenous human chorionic gonadotropin on nude mice bearing endometrial carcinoma].

OBJECTIVE: To observe the effects of exogenous human chorionic gonadotropin (hCG) on nude mice bearing transplanted endometrial carcinoma. METHODS: Human endometrial carcinoma xenograft was transplanted in nude mice, and the effects of hCG injection on the tumor growth was evaluated according to tumorigenesis and xenograft weights. The expression of Ki-67 in the tumor was determined by immunohistochemistry, and HE staining was performed for morphological observation and measurement of the necrosis area in the tumor. The effect of hCG on fibrosis in the tumor was evaluated with Masson staining. RESULTS: Compared to normal saline-treated tumor-bearing mice, the mice with hCG treatment showed increased tumor weight. HE staining for tumors in HCG-treatment group visualized tumor cell arrangement in glandular structure with smaller necrosis area, and Masson staining identified thick and compact collagen fibers as compared with the thin and loosely arranged fibers in saline-treated group. No significant difference was found in the Ki-67 expression in the tumors between the two groups. CONCLUSION: Exogenous hCG can promote the differentiation of the endometrial carcinoma cells in vivo.

[Association of p16, p53, Ki-67 expressions with high-risk human papilloma virus infection in cervical intraepithelial neoplasia].

OBJECTIVE: To investigate the association between p16, p53 and Ki-67 expression and high-risk human papilloma virus (HPV) infection in cervical intraepithelial neoplasia (CIN). METHODS: Using a self-prepared tissue microarray, p16, p53, and Ki-67 expression was detected in 243 cases of CIN and 30 cases of normal cervical epitheliums by immunohistochemistry, and high-risk HPV infection was detected by gene hybridization capture II. RESULTS: p16, p53 and Ki-67 expressions were all negative in normal cervical epitheliums, but all positive in CIN. The expression of p16 and Ki-67 was 88.2 (67/76) and 92.1% (70/76) in CIN grade 1, respectively, and both were 100% in CIN grades 2 and 3, and the intensity of positive expression was significantly correlated with CIN grade (P<0.001). The positive cells in CIN grade 1 were mostly within the lower 1/3 of the squamous epithelium, while in CIN grade 2, the positive cells involved the lower 2/3 of the epithelium layers; in CIN grade 3, more than 2/3 or almost the full thickness of the epithelium was involved, suggesting significant correlation between the involvement and CIN grades (P<0.001). p53 expression was positive in 31.6% (24/76) of the cases in CIN grade 1, 53.4% (47/88) in CIN grade 2 and 58.2% (46/79) in CIN grade 3, and the intensity of positive expression was in significantly correlation with CIN grades (P<0.001), but no significant difference occurred between CIN 2 and CIN 3. High-risk HPV were detected in 37/52 (71.2%) of the cases in CIN grade 1, 50/58 (86.2%) in CIN 2 and 50/55 (90.9%) in CIN 3, and the relative DNA amount was significantly correlated with CIN grade (P<0.001), but there as no significant difference between CIN 2 and CIN 3. CONCLUSIONS: High-risk HPV infection and p16, p53, Ki-67 overexpression all play important roles in the carcinogenesis of cervical precancerous lesion, and both p16 and Ki-67 expression are useful markers in diagnosis and staging of CIN.