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Liang H.,Beihai Institute of Endocrine and Metabolic Diseases | Zhong Y.,Beihai Institute of Endocrine and Metabolic Diseases | Zhou S.,Beihai Institute of Endocrine and Metabolic Diseases | Peng L.,Southern Medical University
Cancer Letters | Year: 2011

The receptor for advanced glycation end-products (RAGE) is a transmembrane receptor in cells, and the interaction of RAGE with ligands results in pro-inflammatory gene activation. Aberrant RAGE activation was reported to promote the pathogenesis of colorectal cancer. This study aimed to investigate the effects of RAGE on the regulation of cell viability, invasion, and angiogenesis, as well as the underlying molecular mechanisms regulating these interactions in colorectal cancer cells. The RAGE mRNA and protein were evaluated in five colorectal cancer cell lines and in 45 cases of colorectal cancer tissue specimens (using immuohistochemistry). RAGE expression was then knockdown using RAGE shRNA for assessing cell viability and invasion assays as well as for tube formation and CAM assays in human umbilical vein endothelial cells and chick embryos, respectively. RAGE was highly expressed in colorectal cancer tissues, and was associated with increased microvessel density. Two of the four RAGE shRNA constructs were able to significantly knockdown RAGE expression in SW480 cells. RAGE knockdown inhibited invasion capacity of SW480 cells, but did not significantly affect cell viability. Furthermore, the conditioned growth medium from stable RAGE shRNA-transfected cells suppressed tube formation of human umbilical vein endothelial cells and angiogenesis of chicken embryos. Knockdown of RAGE inhibited expression of VEGF and SP1 protein in colorectal cancer cells. In summary, these data suggest that silence of RAGE expression could effectively inhibit colorectal cancer angiogenesis in vitro and in vivo. © 2011 Elsevier Ireland Ltd.

Li Q.Q.,U.S. National Institutes of Health | Li Q.Q.,West Virginia University | Lee R.X.,West Virginia University | Liang H.,Beihai Institute of Endocrine and Metabolic Diseases | And 5 more authors.
International Journal of Oncology | Year: 2013

β-Elemene is a promising new plant-derived drug with broad-spectrum anticancer activity. It also increases cisplatin cytotoxicity and enhances cisplatin sensitivity in resistant human carcinoma cells. However, little is known about the mechanism of its action. To explore the potential therapeutic application of β-elemene as a drug-resistance modulator, this study investigated the underlying mechanism of β-elemene activity in cisplatin-resistant ovarian cancer cells. β-Elemene enhanced cisplatin sensitivity to a much greater extent in chemoresistant A2780/CP70 and MCAS human ovarian carcinoma cells compared to the chemosensitive parental cell line A2780. The dose-modifying factors for cisplatin were between 35 and 60 for A2780/CP70 cells and between 1.6 and 2.5 for A2780 cells. In the cisplatin-resistant ovarian carcinoma cells, β-elemene abrogated cisplatin-induced expression of excision repair cross-complementation group-1 (ERCC-1), a marker gene in the nucleotide excision repair pathway that repairs cisplatin-caused DNA damage. In addition, β-elemene not only reduced the level of X-linked inhibitor of apoptosis protein (XIAP), but also downregulated cisplatin-mediated XIAP expression in chemoresistant cells. Furthermore, β-elemene blocked the cisplatin-stimulated increase in the level of phosphorylated c-Jun NH2-terminal kinase (JNK) in these cells. These novel findings suggest that the β-elemene enhancement of cisplatin sensitivity in human chemoresistant ovarian cancer cells is mediated at least in part through the impairment of DNA repair activity and the activation of apoptotic signaling pathways, thereby making resistant ovarian cancer cells susceptible to cisplatin-induced cell death.

Liang H.,Beihai Institute of Endocrine and Metabolic Diseases | Zhong Y.,Beihai Institute of Endocrine and Metabolic Diseases | Huang Y.,Peoples Hospital of Guangxi Autonomous Region | Chen G.,Chaoan Peoples Hospital
Medical Oncology | Year: 2012

Increased breast cancer incidence parallels the increase in cases of type 2 diabetes. We investigated the effect of type 1 receptor parathyroid hormone (PTH1R) expression on viability and apoptosis of breast cancer cells exposed to high levels of glucose. Upregulation of PTH1R was detected in patients with invasive ductal carcinoma of the breast and diabetes. In vitro, PTH1R silencing suppressed cell proliferation and apoptosis induced by high levels of glucose by regulating Bax/Bcl-2 expression. These results suggest PTH1R silencing may represent a novel treatment approach for patients diagnosed with invasive ductal carcinoma of the breast who are also managing diabetes. © Springer Science+Business Media, LLC 2011.

Quentin Li Q.,U.S. National Institutes of Health | Quentin Li Q.,West Virginia University | Wang G.,West Virginia University | Liang H.,Beihai Institute of Endocrine and Metabolic Diseases | And 6 more authors.
Anticancer Research | Year: 2013

Cisplatin-based combination treatment is the most effective systemic chemotherapy for bladder cancer; however, resistance to cisplatin remains a significant problem in the treatment of this disease. β-Elemene is a new natural compound that blocks cell-cycle progression and has a broad spectrum of antitumor activity. This study was conducted to explore the potential of β-elemene as a chemosensitizer for enhancing the therapeutic efficacy and potency of cisplatin in bladder cancer and other solid carcinomas. β-Elemene not only markedly inhibited cell growth and proliferation but also substantially increased cisplatin cytotoxicity towards human bladder cancer 5637 and T-24 cells. Similarly, β-elemene also enhanced cisplatin sensitivity and augmented cisplatin cytotoxicity in small-cell lung cancer and carcinomas of the brain, breast, cervix, ovary, and colorectal tract in vitro, with dose-modifying factors ranging from 5 to 124. β-Elemene-enhanced cisplatin cytotoxicity was associated with increased apoptotic cell death, as determined by DNA fragmentation, and increased activities of caspase-3, -7, -8, -9, and -10 in bladder cancer cell lines. Collectively, these results suggest that β-elemene augments the antitumor activity of cisplatin in human bladder cancer by enhancing the induction of cellular apoptosis via a caspase-dependent mechanism. Cisplatin combined with β-elemene as a chemosensitizer warrants further pre-clinical therapeutic studies and may be useful for the treatment of cisplatin-resistant bladder cancer and other types of carcinomas.

Li Q.Q.,Beihai Institute of Endocrine and Metabolic Diseases | Li Q.Q.,West Virginia University | Li Q.Q.,U.S. National Institutes of Health | Lee R.X.,West Virginia University | And 3 more authors.
Medical Oncology | Year: 2013

β-Elemene is a new anticancer compound extracted from the Chinese medicinal herb Rhizoma zedoariae. We have shown previously that β-elemene increases cisplatin cytotoxicity and enhances cisplatin sensitivity via blocking cell cycle progression at G2/M phase in resistant ovarian tumor cells. In the current study, we asked whether β-elemene-augmented cisplatin activity in ovarian carcinoma cells is mediated through the induction of apoptosis. Here, we show that β-elemene triggered apoptotic cell death in chemoresistant human ovarian cancer A2780/CP and MCAS cells in a dose- and time-dependent fashion, as assessed by six different apoptosis assays. Intriguingly, β-elemene was a stronger inducer of apoptosis than cisplatin in this model system, and a synergistic effect on induction of cell death was observed when the tumor cells were treated with both agents. Furthermore, β-elemene plus cisplatin exposure significantly disrupted the mitochondrial transmembrane potential (ΔΨ m) and increased the release of cytochrome c from mitochondria into the cytoplasm. The combination treatment with both compounds also induced increases in caspase-3/8/9 activities and caspase-9 cleavage, enhanced protein expression of Bax and phosphorylation of Bcl-2 at Ser-70, and reduced the protein levels of Bcl-2 and Bcl-XL in the platinum-resistant ovarian cancer cells. Taken together, these data indicate that β-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced apoptosis and that the augmented effect of β-elemene on cisplatin cytotoxicity and sensitivity in resistant ovarian tumor cells is mediated through a mitochondria- and caspase-dependent cell death pathway. © 2012 Springer Science+Business Media New York.

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