Shailubhai Kunwar, Dheer Surendra, Picker Donald, Kaur Gurmeet, Sausville Edward A, Jacob Gary S
Callisto Pharmaceuticals, Inc, 420 Lexington Avenue, Suite 1609, New York, NY 10170, USA.
J Exp Ther Oncol. 2004 Dec;4(4):267-79.
Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have also shown that atiprimod treatment reduced production of IL-6, VEGF and inhibited activation of Stat3, a constitutively activated protein in majority of human cancers. Together these findings suggest that atiprimod acts on several molecules that are essential for tumor growth, invasion and metastasis.
阿替普莫德是一种属于氮杂螺烷类阳离子两亲性药物的新型化合物，具有抗增殖和抗血管生成活性。阿替普莫德抑制了美国国立癌症研究所筛选的所有人类癌细胞系的增殖，其半数抑制浓度（IC50）值处于低微摩尔范围。值得注意的是，与源自相同肿瘤组织类型的非转移性细胞系相比，转移性细胞系对该化合物更为敏感。阿替普莫德还可诱导T84结肠癌细胞凋亡，并激活半胱天冬酶-9和半胱天冬酶-3。因此，其抗增殖活性部分可能归因于促凋亡活性。在体外血管生成方面，阿替普莫德抑制碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）诱导的人脐静脉内皮细胞（HUVECs）增殖和迁移，导致条索形成中断。此外，在鸡胚绒毛尿囊膜试验中，阿替普莫德也抑制了新血管的形成。先前的研究还表明，阿替普莫德治疗可降低白细胞介素-6（IL-6）、VEGF的产生，并抑制信号转导和转录激活因子3（Stat3）的激活，Stat3是大多数人类癌症中一种持续激活的蛋白。这些研究结果共同表明，阿替普莫德作用于肿瘤生长、侵袭和转移所必需的多种分子。
