全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...

Tasquinimod (ABR-215050), a quinoline-3-carboxamide anti-angiogenic agent, modulates the expression of thrombospondin-1 in human prostate tumors

DOI: 10.1186/1476-4598-9-107

Full-Text   Cite this paper   Add to My Lib

Abstract:

One of the most significant differentially expressed genes both in vitro and in vivo after exposure to tasquinimod, was thrombospondin-1 (TSP1). The up-regulation of TSP1 mRNA in LNCaP tumor cells both in vitro and in vivo correlated with an increased expression and extra cellular secretion of TSP1 protein. When nude mice bearing CWR-22RH human prostate tumors were treated with oral tasquinimod, there was a profound growth inhibition, associated with an up-regulation of TSP1 and a down- regulation of HIF-1 alpha protein, androgen receptor protein (AR) and glucose transporter-1 protein within the tumor tissue. Changes in TSP1 expression were paralleled by an anti-angiogenic response, as documented by decreased or unchanged tumor tissue levels of VEGF (a HIF-1 alpha down stream target) in the tumors from tasquinimod treated mice.We conclude that tasquinimod-induced up-regulation of TSP1 is part of a mechanism involving down-regulation of HIF1α and VEGF, which in turn leads to reduced angiogenesis via inhibition of the "angiogenic switch", that could explain tasquinimods therapeutic potential.During the last decades, development of new cancer treatments that are capable of inhibiting tumor growth by inhibition of the blood supply has received great attention [1,2]. The quinoline compound tasquinimod [ABR-215050; CAS number 254964-60-8; 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[(4-trifluoromethyl) phenyl]-1,2-dihydroquinoline-3-carboxamide] has emerged as a candidate [3], by virtue of its pharmacological profile with anti-angiogenic and anti-tumor potency in experimental human prostate cancer models [4,5]. Thrombospondin-1 (TSP1) is a 450 kDa glycoprotein initially found in platelets, but also synthesized and secreted by many normal and transformed cells. TSP1 has been shown to be a potent natural inhibitor of tumor progression and metastases via inhibition of angiogenesis and migration or by activation of TGFβ (for review see [6-8]). Several mechanisms have been propos

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133