Vitamin E δ-tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF-κB activation in pancreatic cancer.
Vitamin E δ-tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF-κB activation in pancreatic cancer.
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DOI：
10.1158/1535-7163.mct-11-0424
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发表时间：
2011-12
影响因子：
5.7
通讯作者：
Malafa MP
中科院分区：
文献类型：
--
作者：
Husain K;Francois RA;Yamauchi T;Perez M;Sebti SM;Malafa MP
核因子-κB (NF-κB) 转录因子是胰腺癌细胞存活和化疗耐药性的关键调节因子。最近的研究表明，生育三烯酚是维生素 E 的不饱和形式，是一类很有前途的抗癌化合物，可以抑制许多癌细胞（包括胰腺癌）的生长和存活。在这里，我们证明生育三烯酚在体外和体内抑制 NF-κB 活性和人胰腺癌细胞的存活。重要的是，我们发现 4 种天然生育三烯酚化合物（α-、β-、δ- 和 γ-生育三烯酚）的生物活性与其在体外和体内抑制 NF-κB 活性的能力直接相关。对胰腺癌最具生物活性的生育三烯酚，δ-生育三烯酚，显着增强了吉西他滨在体外和体内抑制胰腺癌生长和存活的功效。此外，我们发现 δ-生育三烯酚在胰腺癌细胞和肿瘤中增强吉西他滨活性与显着抑制 NF-κB 活性和 NF-κB 转录靶标 [Bcl-XL、X 连锁凋亡抑制剂 (XIAP) 和生存素] 的表达相关。我们的研究首次对天然维生素 E 化合物在胰腺癌中的活性进行了全面的临床前评估。鉴于这些结果，我们正在胰腺癌患者中进行 δ-生育三烯酚的 I 期试验，利用胰腺肿瘤细胞存活和 NF-κB 信号成分作为中间生物标志物。我们的数据还支持未来 δ-生育三烯酚的临床研究，以增强吉西他滨在胰腺癌中的活性。
The nuclear factor-κB (NF-κB) transcription factor functions as a crucial regulator of cell survival and chemoresistance in pancreatic cancer. Recent studies suggest that tocotrienols, which are the unsaturated forms of vitamin E, are a promising class of anti-cancer compounds that inhibit the growth and survival of many cancer cells, including pancreatic cancer. Here, we show that tocotrienols inhibited NF-κB activity and the survival of human pancreatic cancer cells in vitro and in vivo. Importantly, we found the bioactivity of the 4 natural tocotrienol compounds (α-, β-, δ-, and γ-tocotrienol) to be directly related to their ability to suppress NF-κB activity in vitro and in vivo. The most bioactive tocotrienol for pancreatic cancer, δ-tocotrienol, significantly enhanced the efficacy of gemcitabine to inhibit pancreatic cancer growth and survival in vitro and in vivo. Moreover, we found that δ-tocotrienol augmentation of gemcitabine activity in pancreatic cancer cells and tumors is associated with significant suppression of NF-κB activity and the expression of NF-κB transcriptional targets [Bcl-XL, X-linked inhibitor of apoptosis (XIAP), and survivin]. Our study represents the first comprehensive pre-clinical evaluation of the activity of natural vitamin E compounds in pancreatic cancer. Given these results, we are conducting a phase I trial of δ-tocotrienol in patients with pancreatic cancer utilizing pancreatic tumor cell survival and NF-κB signaling components as intermediate biomarkers. Our data also support future clinical investigation of δ-tocotrienol to augment gemcitabine activity in pancreatic cancer.