Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts.
Doxorubicin increases the effectiveness of Apo2L/TRAIL for tumor growth inhibition of prostate cancer xenografts.
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DOI：
10.1186/1471-2407-5-2
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发表时间：
2005-01-07
期刊：
影响因子：
3.8
通讯作者：
Voelkel-Johnson C
中科院分区：
文献类型：
--
作者：
El-Zawahry A;McKillop J;Voelkel-Johnson C
前列腺癌是美国男性的一个重大健康问题。雄激素非依赖性癌症的治疗策略目前尚不可用。肿瘤坏死因子相关凋亡诱导配体（Apo 2L/TRAIL）是一种死亡受体配体，可诱导多种癌细胞系的凋亡，包括雄激素非依赖性前列腺癌PC 3细胞。在体外，TRAIL介导的前列腺癌细胞系的凋亡可以通过阿霉素增强，并且与抗凋亡蛋白c-FLIP的下调相关。本研究评价了阿霉素与Apo 2L/TRAIL联合应用对异种移植模型中c-FLIP表达和肿瘤生长的影响。使用基于MTS的活力测定来测量TRAIL的体外细胞毒性作用。对于体内研究，使PC 3前列腺癌细胞在无胸腺裸鼠中皮下生长，并在用多柔比星和/或Apo 2L/TRAIL处理后测量肿瘤生长。通过蛋白质印迹分析测定c-FLIP表达。TUNEL法检测移植瘤细胞凋亡。使用学生t检验进行统计分析。体外实验表明，PC 3细胞对Apo 2L/TRAIL部分敏感，阿霉素增强了这种敏感性。在小鼠中，多柔比星没有显著影响PC 3异种移植物的生长，但降低了肿瘤中的c-FLIP表达。小鼠心脏中c-FLIP的表达仅在高阿霉素浓度（8 mg/kg）下降低。阿霉素与Apo 2L/TRAIL的组合比单独的Apo 2L/TRAIL导致更多的凋亡细胞死亡和肿瘤生长抑制。多柔比星和Apo 2L/TRAIL的组合在体内PC 3异种移植物的生长抑制中比单独的任一种药剂更有效，并且可以提出针对难治性前列腺癌的新的治疗策略。阿霉素增强Apo 2L/TRAIL对PC 3异种移植物的作用的细胞内机制可能是通过减少c-FLIP的表达。
Prostate cancer is a significant health problem among American men. Treatment strategies for androgen-independent cancer are currently not available. Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, including androgen-independent PC3 prostate carcinoma cells. In vitro, TRAIL-mediated apoptosis of prostate cancer cell lines can be enhanced by doxorubicin and correlates with the downregulation of the anti-apoptotic protein c-FLIP. This study evaluated the effects of doxorubicin on c-FLIP expression and tumor growth in combination with Apo2L/TRAIL in a xenograft model. In vitro cytotoxic effects of TRAIL were measured using a MTS-based viability assay. For in vivo studies, PC3 prostate carcinoma cells were grown subcutaneously in athymic nude mice and tumor growth was measured following treatment with doxorubicin and/or Apo2L/TRAIL. c-FLIP expression was determined by western blot analysis. Apoptosis in xenografts was detected using TUNEL. Statistical analysis was performed using the student t-test. In vitro experiments show that PC3 cells are partially susceptible to Apo2L/TRAIL and that susceptibility is enhanced by doxorubicin. In mice, doxorubicin did not significantly affect the growth of PC3 xenografts but reduced c-FLIP expression in tumors. Expression of c-FLIP in mouse heart was decreased only at the high doxorubicin concentration (8 mg/kg). Combination of doxorubicin with Apo2L/TRAIL resulted in more apoptotic cell death and tumor growth inhibition than Apo2L/TRAIL alone. Combination of doxorubicin and Apo2L/TRAIL is more effective in growth inhibition of PC3 xenografts in vivo than either agent alone and could present a novel treatment strategy against hormone-refractory prostate cancer. The intracellular mechanism by which doxorubicin enhances the effect of Apo2L/TRAIL on PC3 xenografts may be by reducing expression of c-FLIP.
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影响因子：
20.3
作者：
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通讯作者：
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