Nawrocki Steffan T, Sweeney-Gotsch Bridget, Takamori Ryan, McConkey David J
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mol Cancer Ther. 2004 Jan;3(1):59-70.
Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative, which is a selective and potent inhibitor of the proteasome. We examined the antitumor activity of combination therapy with bortezomib + docetaxel in two human pancreatic cancer cell lines (MiaPaCa-2 and L3.6pl) selected for their divergent responses to bortezomib alone. Bortezomib blocked docetaxel-induced apoptosis in the MiaPaCa-2 cells and failed to enhance docetaxel-induced apoptosis in L3.6pl cells in vitro but did interact positively with docetaxel to inhibit clonogenic survival. These effects were associated with decreased accumulation of cells in M phase, stabilization of the cyclin-dependent kinase inhibitors, p21 and p27, and inhibition of cdk2 and cdc2 activities. In orthotopic xenografts, combination therapy produced significant reductions in tumor weight and volume in both models associated with accumulation of p21, inhibition of proliferation, and increased apoptosis. Combination therapy also reduced tumor microvessel densities, effects that were associated with reductions in tumor cell production of vascular endothelial growth factor and increased levels of apoptosis in tumor-associated endothelial cells. Together, our results suggest that bortezomib enhances the antitumoral activity of taxanes by enforcing cell growth arrest and inhibiting angiogenesis.
硼替佐米（万珂，原名PS - 341）是一种硼酸二肽衍生物，是一种选择性且强效的蛋白酶体抑制剂。我们选用了两种对单独使用硼替佐米反应不同的人胰腺癌细胞系（MiaPaCa - 2和L3.6pl），研究了硼替佐米联合多西他赛的抗肿瘤活性。硼替佐米在体外阻断了多西他赛诱导的MiaPaCa - 2细胞凋亡，未能增强多西他赛诱导的L3.6pl细胞凋亡，但确实与多西他赛产生正向相互作用以抑制克隆形成存活。这些效应与M期细胞积累减少、细胞周期蛋白依赖性激酶抑制剂p21和p27的稳定以及cdk2和cdc2活性的抑制有关。在原位异种移植模型中，联合治疗在两个模型中均使肿瘤重量和体积显著降低，这与p21的积累、增殖抑制和凋亡增加有关。联合治疗还降低了肿瘤微血管密度，这些效应与肿瘤细胞血管内皮生长因子产生减少以及肿瘤相关内皮细胞凋亡水平增加有关。总之，我们的结果表明硼替佐米通过加强细胞生长停滞和抑制血管生成来增强紫杉烷类的抗肿瘤活性。
