Abstract
Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer. Active constituents derived from Chinese medicine with anti-cancer potential might circumvent this obstacle. In our present study, evodiamine (EVO) derived from Evodia rutaecarpa (Juss.) Benth suppressed the proliferation of human epithelial ovarian cancer, A2780 and the related paclitaxel-resistant cell lines and did not cause cytotoxicity, as confirmed by the significant decline of clone formation and the representative alterations of CFDA-SE fluorescence. Meanwhile, EVO induced cell cycle arrest in a dose- and time-dependent manner. This disturbance might be mediated by the cooperation of Cyclin B1 and Cdc2, including the up-regulation of Cyclin B1, p27, and p21, and activation failure of Cdc2 and pRb. MAPK signaling pathway regulation also assisted in this process. Furthermore, chemo-sensitivity potential was enhanced as indicated in A2780/PTXR cells by the down-regulation of MDR-1 expression, accompanied by MDR-1 function suppression. Taken together, we confirmed initially that EVO exerted an anti-proliferative effect on human epithelial ovarian cancer cells, A2780/WT and A2780/PTXR, induced G2/M phase cell cycle arrest, and improved chemo-resistance. Overall, we found that EVO significantly suppressed malignant proliferation in human epithelial ovarian cancer, thus proving to be a potential anti-cancer agent in the future.
Highlights
Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer
Since the year 2000 when X-linked inhibitors for apoptotic proteins (Xiap) assisted by p53 status were regarded as important targets for chemo-resistance in human ovarian epithelial cancer[1], extensive investigations have concentrated on Xiap and the PI3K/Akt pathway[2,3], BRCA1/2 alterations[4], epithelial mesenchymal transition and cancerous ovarian stem cells[5,6], and even considered metabolic alterations and epigenetic therapies[7,8], in order to circumvent chemo-resistance
Those results showed that A2780/PTXR cells were resistant to paclitaxel, with an IC50 value of 550.9 μ M
Summary
Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer. Cyclin B1 is another important regulatory protein in the cell cycle, and it interacts with Cdc[2] to form the cyclin B1-Cdk[1] complex, promoting mitotic initiation[14] These proteins prefer to over-express in low-malignant-potential tumors rather than epithelial ovarian cancer to develop tumorigenesis[15]. P27 and p21 are regarded as potential tumor suppressors, and low levels of p27 and high levels of phospho-Rb were found to significantly correlate with poor patient survival in ovarian cancer[16] Rb is another signature for human high-grade serous epithelial ovarian cancer[17], and it is phosphorylated by cyclin D kinases to lead to progression into the S phase of the cell cycle[18]. P-glycoprotein (P-gp) expression and function are clinically significant in patients with ovarian cancer therapy[21]
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