CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer.
CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer.
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DOI：
10.3390/cancers2041779
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发表时间：
2010-12
期刊：
影响因子：
5.2
通讯作者：
Gautam SC
中科院分区：
文献类型：
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作者：
Deeb D;Gao X;Arbab AS;Barton K;Dulchavsky SA;Gautam SC
胰腺导管腺癌（PDA）是人类最致命的恶性肿瘤之一，预后差，有效的治疗方法很少。迫切需要安全有效的新型药物。油酸衍生的合成三萜类化合物是有效的抗肿瘤剂，但其对胰腺癌的疗效或作用机制尚未得到充分研究。在这项研究中，我们评估了甲基-2-氰基-3，12-dioxooleana-1，9（11）-dien-28-oate（CDDO-Me），一种齐墩果烷衍生的合成三萜类化合物对人胰腺癌细胞系的抗肿瘤活性和作用机制。CDDO-Me在非常低的浓度下抑制K-ras突变（MiaPaca 2、Panc 1和Capan 2）和野生型K-ras（BxPC 3）胰腺癌细胞的生长。CDDO-Me的生长抑制活性归因于诱导细胞凋亡，其特征在于膜联蛋白-V-FITC结合增加以及PARP-1和半胱氨酸蛋白酶原-3、-8和-9的裂解。此外，CDDO-Me诱导线粒体膜电位的损失和细胞色素C的释放。CDDO-Me的抗肿瘤活性与抑制促存活蛋白p-Akt、NF-κB和哺乳动物雷帕霉素靶蛋白（mTOR）信号传导蛋白以及Akt和mTOR的下游靶点如p-Foxo 3a（Akt）和p-S6 K1、p-eIF-4 E和p-4 E-BP 1（mTOR）有关。用基因特异性siRNA沉默Akt或mTOR使胰腺癌细胞对CDDO-Me敏感，证明Akt和mTOR是CDDO-Me的生长抑制和凋亡诱导活性的分子靶点。
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.