Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo
Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo
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DOI：
10.1002/pros.20126
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发表时间：
2005-02-01
期刊：
影响因子：
2.8
通讯作者：
Srivastava, RK
中科院分区：
文献类型：
--
作者：
Shankar, S;Chen, XF;Srivastava, RK
背景。肿瘤坏死因子相关凋亡诱导配体/Apo2配体（TRAIL/Apo-2L）是一种新型抗癌药物，在肿瘤和转化细胞中具有优先诱导凋亡的功能。TRAIL- r1 /死亡受体（DR）4和TRAIL- r2 /DR5是肿瘤坏死因子（TNF）受体家族的成员，可以被TRAIL激活。我们考察了化疗药物和TRAIL治疗前列腺癌的临床潜力。前列腺癌和膀胱癌细胞暴露于化疗药物（紫杉醇、长春新碱、长春花碱、依托泊苷、阿霉素和喜树碱）和TRAIL。采用3′[1-（苯胺羰基）-3,4-四唑]-双（4-甲氧基-6-硝基）钠法测定细胞活力；采用Western blotting、ELISA和核糖核酸酶保护实验检测死亡受体和Bcl-2家族成员的表达。将异种移植PC-3肿瘤细胞的胸腺裸鼠单独或联合暴露于化疗药物和TRAIL中，测量小鼠肿瘤的生长和存活情况。annexin V-FITC/碘化丙啶染色和末端脱氧核苷酸转移酶介导的缺口末端标记法检测细胞凋亡。Western blotting和免疫组织化学检测Caspase-3活性。TRAIL诱导不同敏感性的细胞凋亡。化疗药物（紫杉醇、长春新碱、长春花碱、依托泊苷、阿霉素和喜树碱）通过上调DR4、DR5、Bax和Bak，以及诱导caspase活化，显著增强trail诱导的癌细胞凋亡。线粒体途径增强了药物与TRAIL之间的协同作用。化疗药物序贯治疗小鼠后，TRAIL诱导caspase-3活性和凋亡，抑制血管生成，完全根除已形成的肿瘤，提高小鼠存活率。化疗药物可用于提高TRAIL在前列腺癌中的治疗潜力。(C) 2004 Wiley-Liss, Inc。
BACKGROUND. Tumor necrosis factor related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo-2L) is a novel anticancer agent, capable of inducing apoptosis preferentially in tumor and transformed cells. TRAIL-R1/death receptor (DR)4 and TRAIL-R2/DR5 are members of the tumor necrosis factor (TNF) receptor family, and can be activated by the TRAIL. We examined the clinical potential of chemotherapeutic drugs and TRAIL for the treatment of prostate cancer.METHODS. Prostate and bladder cancer cells were exposed to chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, doxorubicin, and camptothecin) and TRAIL. Cell viability was measured by sodium 3'[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) assay; expressions of death receptors and Bcl-2 family members were measured by Western blotting, ELISA and ribonuclease protection assay. PC-3 tumor cells xenografted athymic nude mice were exposed to chemotherapeutic drugs and TRAIL, either alone or in combination, to measure tumor growth and survival of mice. Apoptosis was measured by annexin V-FITC/propidium iodide staining, and terminal deoxynucleotidyltransferase-mediated nick end labeling assay. Caspase-3 activity was measured by the Western blotting and immunohistochemistry.RESULTS. TRAIL induced apoptosis with varying sensitivity. Chemotherapeutic drugs (paclitaxel, vincristine, vinblastine, etoposide, doxorubicin, and camptothecin) significantly augmented TRAIL-induced apoptosis in cancer cells through up-regulation of DR4, DR5, Bax, and Bak, and induction of caspase activation. Mitochondrial pathway enhanced the synergistic interactions between drugs and TRAIL. The sequential treatment of mice with chemotherapeutic drugs followed by TRAIL induced caspase-3 activity, and apoptosis, inhibited angiogenesis, completely eradicated the established tumors, and enhanced survival of mice.CONCLUSIONS. Chemotherapeutic drugs can be used to enhance the therapeutic potential of TRAIL in prostate cancer. (C) 2004 Wiley-Liss, Inc.