Study for therapeutic effects and mechanisms of Wedelia chinensis extract on prostate cancer
| Autor: | Chin-Hsien Tsai, 蔡進賢 |
|---|---|
| Rok vydání: | 2014 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 102 Recurrences of hormone-refractory and metastatic prostate cancer (PCa) both highly affect the treatment outcome. Developing the orthotopic PCa animal model to study the cancer progression and effective therapy is the critical mission. Here, we established the orthotopic xenograft mouse model of PCa cell line, 22Rv1, cultured the different stages of tumor cells, and repeated the same procedure to get highly metastatic cells. In this model, we found that HAI-2, a matriptase inhibitor, is decreased during PCa progression, which enhanced the invasive growth and metastasis capacity of PCa cells. This effect was reversed by either ectopic expression of HAI-2 or matriptase knockdown, indicating that derepression of matriptase from HAI-2 contributed to the cancer metastasis. Besides, we used Prostatic Specific Antigen (PSA) promoter activity assay to identify the principal active compounds (wedelolectone, luteolin, and apigenin) in the herbal ethanol extract of Wedelia chinensis and demonstrated the active compounds synergistically inhibited AR-positive PCa cell growth in vitro and in vivo. To promote the potential clinical use as a botanical drug, we developed a standardized preparation of a W. chinensis extract (WCE) by enrichment and quantification of the principal active compounds and analyses of the in vivo biological activities. Pharmacokinetic analyses of active compounds upon oral administration with WCE indicated that presence of copurifiied other compounds in WCE prolonged the systemic exposure to active compounds over a formula of the pure active compounds. In agreement, the resulting anti-tumor efficacy of WCE was higher than the formula of pure active compounds. Furthermore, WCE effectively disrupted the androgen receptor, HER2/3, and AKT signaling network and therefore enhanced therapeutic efficacy of androgen ablation in PCa. While HER2/3 and AKT inhibition by WCE failed to induce apoptosis in hormone-refractory PCa cells, WCE curbed PCa-induced chemotaxis of myeloid cells and the tumor-microenvironment interactions, thus impairing PCa growth and metastasis. In conclusion, the imbalance between HAI-2 and matriptase expression led to matriptase activation, thereby increasing PCa metastasis. In herbal medicine study, we demonstrated that standardized, characterized preparations of WCE improved the outcome of PCa therapy either as an add-on to hormonal therapy for androgen-dependent disease or as a monotherapy for hormone-refractory disease. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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