Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms
Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms
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DOI：
10.1158/1535-7163.mct-08-0216
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Srivastava, Rakesh K.
中科院分区：
文献类型：
--
作者：
Shankar, Sharmila;Chen, Qinghe;Srivastava, Rakesh K.
最近的研究表明，天然存在的化合物可以增强化疗药物的功效。本研究的目的是探讨二烯丙基三硫化物 (DATS) 增强肿瘤坏死因子相关凋亡包含配体 (TRAIL) 在体外前列腺癌细胞和裸鼠原位移植 PC-3 前列腺癌中的治疗潜力的分子机制。 DATS 抑制 PC-3 和 LNCaP 细胞的细胞活力和集落形成并诱导细胞凋亡。 DATS 增强了 PC-3 细胞中 TRAIL 的凋亡诱导潜力，并使 TRAIL 耐药的 LNCaP 细胞变得敏感。显性失活 FADD 抑制 DATS 和 TRAIL 对细胞凋亡的协同作用。 DATS 诱导 DR4、DR5、Bax、Bak、Bim、Noxa 和 PUMA 的表达，并抑制 Mcl-1、Bcl-2、Bcl-X-L、survivin、XIAP、cIAP1 和 cIAP2 的表达。与对照组相比，口服DATS显着抑制BALB/c裸鼠原位种植的前列腺癌的生长，且不引起体重减轻。与单独使用任一药物相比，用 DATS 和 TRAIL 联合治疗小鼠在抑制前列腺肿瘤生长以及诱导 DR4 和 DR5 表达、caspase-8 活性和细胞凋亡方面更有效。 DATS 抑制血管生成（通过 CD31 阳性和因子 VIII 阳性血管以及缺氧诱导因子 1 α、血管内皮生长因子和白细胞介素 6 表达来测量）和转移[基质金属蛋白酶 (MMP)-2、MMP-7、MMP-9 和 MT-1 MMP 表达]，这与抑制 AKT 和核因子-κ B 激活相关。 DATS 和 TRAIL 的组合在抑制血管生成和转移标志物方面比单独使用任何一种药物更有效。这些数据表明 DATS 可以与 TRAIL 联合用于预防和/或治疗前列腺癌。
Recent studies have shown that naturally occurring compounds can enhance the efficacy of chemotherapeutic drugs. The objectives of this study were to investigate the molecular mechanisms by which diallyl trisulfide (DATS) enhanced the therapeutic potential of tumor necrosis factor-related apoptosis-inclucing ligand (TRAIL) in prostate cancer cells in vitro and on orthotopically transplanted PC-3 prostate carcinoma in nude mice. DATS inhibited cell viability and colony formation and induced apoptosis in PC-3 and LNCaP cells. DATS enhanced the apoptosis-inducing potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Dominant-negative FADD inhibited the synergistic interaction between DATS and TRAIL on apoptosis. DATS induced the expression of DR4, DR5, Bax, Bak, Bim, Noxa, and PUMA and inhibited expression of Mcl-1, Bcl-2, Bcl-X-L, survivin, XIAP, cIAP1, and cIAP2. Oral administration of DATS significantly inhibited growth of orthotopically implanted prostate carcinoma in BALB/c nude mice compared with the control group, without causing weight loss. Cotreatment of mice with DATS and TRAIL was more effective in inhibiting prostate tumor growth and inducing DR4 and DR5 expression, caspase-8 activity, and apoptosis than either agent alone. DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII positive blood vessels and hypoxia-inducible factor-1 alpha., vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappa B activation. The combination of DATS and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis than either agent alone. These data suggest that DATS can be combined with TRAIL for the prevention and/or treatment of prostate cancer.