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.

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Early diagnosis and treatment of thyroid cancers are critical for better prognosis and better survival rates. The purpose of this study was to identify potential diagnostic markers for papillary thyroid carcinomas with distant metastasis. Fifty-eight papillary thyroid tumor specimens (27 papillary thyroid carcinomas with distant metastasis and 31 without metastasis) were examined, and protein expression of pituitary tumor-transforming gene (PTTG), E-cadherin, p27kip1, vascular endothelial growth factor (VEGF)-C, metalloproteinase (MMP) 2, MMP9, chemokine receptor CXCR4, and basic fibroblast growth factor (bFGF) in these tumors was assessed by immunohistochemistry. The clinicopathological variables with diagnostic significance were determined by multivariate analysis, and their diagnostic values were evaluated by ROC curve analysis. PTTG, VEGF-C, MMP2, MMP9, CXCR4, and bFGF were overexpressed in metastatic papillary thyroid carcinomas, whereas p27kip1 expression was elevated only in carcinomas lacking metastasis. Multiple-factor binary ordinal logistic regression analysis revealed that PTTG, VEGF-C, MMP2, and bFGF were independently related to biological metastatic behavior in thyroid tumors, suggesting their potential use as biomarkers. ROC curve analysis showed that among these four proteins, VEGF-C and bFGF were the best diagnostic biomarkers. A VEGF-C and bFGF cluster was the most useful factor for the differential diagnosis between metastatic and non-metastatic papillary thyroid cancers. Thus, the combined use of VEGF-C and bFGF as biomarkers may improve the diagnostic accuracy of papillary thyroid carcinoma and may be useful in multimodal screening programs for the clinical diagnosis of papillary thyroid carcinoma and early detection of papillary thyroid carcinoma with distant metastasis.