Antiproliferative, Antiinvasive, and Proapoptotic Activity of Folate Receptor alpha-Targeted Liposomal Doxorubicin in Nonfunctional Pituitary Adenoma Cells

作者:Liu, Xiaohai; Ma, Sihai; Dai, Congxin; Cai, Feng; Yao, Yong; Yang, Yakun; Feng, Ming; Deng, Kan; Li, Guiling; Ma, Wenbing; Xin, Bing; Lian, Wei; Xiang, Guangya; Zhang, Bo; Wang, Renzhi*
来源:Endocrinology, 2013, 154(4): 1414-1423.
DOI:10.1210/en.2012-2128

摘要

There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)alpha is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FR alpha-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FR alpha and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FR alpha plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FR alpha. (Endocrinology 154: 1414-1423, 2013)