Prevention of Prostate Cancer with Oleanane Synthetic Triterpenoid CDDO-Me in the TRAMP Mouse Model of Prostate Cancer.
Prevention of Prostate Cancer with Oleanane Synthetic Triterpenoid CDDO-Me in the TRAMP Mouse Model of Prostate Cancer.
复制标题
DOI：
10.3390/cancers3033353
复制
发表时间：
2011
期刊：
影响因子：
5.2
通讯作者：
Gautam SC
中科院分区：
文献类型：
--
作者：
Gao X;Deeb D;Liu Y;Arbab AS;Divine GW;Dulchavsky SA;Gautam SC
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid (CDDO) 是齐墩果酸的合成类似物，及其 C28 甲酯衍生物 (CDDO-Me)，在体外对多种癌细胞系（包括前列腺癌细胞）显示出有效的抗肿瘤活性，并在体内抑制肝癌和肺癌的发展。在本研究中，我们在小鼠前列腺转基因腺癌 (TRAMP) 模型中检查了 CDDO-Me 在预防前列腺癌发生和进展方面的功效。 CDDO-Me 通过抑制抗凋亡 p-Akt、p-mTOR 和 NF-κB 诱导细胞凋亡，从而抑制小鼠 TRAMPC-1 前列腺癌细胞的生长。从五周龄开始进行为期 20 周的 CDDO-Me (7.5 mg/kg) 早期干预，抑制了 TRAMP 小鼠背外侧前列腺 (DLP) 和腹侧前列腺 (VP) 叶中的癌前病变 (低级别 PIN 和高级别 PIN) 向腺癌的进展。即使在 12 周龄开始延迟给予 CDDO-Me 12 周，也能抑制前列腺腺癌的发展。 CDDO-Me的早期和晚期治疗均抑制肿瘤向远处器官的转移。 CDDO-Me 治疗抑制了前列腺中促存活 p-Akt 和 NF-κB 的表达，敲低 TRAMPC-1 肿瘤细胞中的 Akt 使它们对 CDDO-Me 敏感。这些发现表明，Akt 是 TRAMPC-1 细胞体外凋亡毒性的靶点，并且可能是 CDDO-Me 体内抑制前列腺癌的靶点。
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with CDDO-Me inhibited the metastasis of tumor to the distant organs. Treatment with CDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1 tumor cells sensitized them to CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of CDDO-Me for inhibition of prostate cancer in vivo.