Department of General Surgery, Henry Ford Health System, Detroit, MI 48150, USA;
Cancers (Basel). 2011;3(3):3353-69. doi: 10.3390/cancers3033353.
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.
2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸（CDDO），一种齐墩果酸的合成类似物，及其 C28 甲酯衍生物（CDDO-Me），对多种癌细胞系具有很强的抗肿瘤活性，包括体外前列腺癌细胞，并抑制体内肝癌和肺癌的发展。在本研究中，我们研究了 CDDO-Me 在预防转基因小鼠前列腺腺癌（TRAMP）模型中前列腺癌发展和进展中的疗效。CDDO-Me 通过抑制抗凋亡的 p-Akt、p-mTOR 和 NF-κB，诱导细胞凋亡，抑制小鼠 TRAMPC-1 前列腺癌细胞的生长。7.5mg/kg 的 CDDO-Me 在 5 周龄时早期干预 20 周，可抑制背外侧前列腺（DLP）和腹侧前列腺（VP）叶的前肿瘤病变（低级别 PIN 和高级别-PIN）向腺癌的进展。即使在 12 周龄时开始延迟给予 CDDO-Me 12 周，也可抑制前列腺腺癌的发展。早期和晚期给予 CDDO-Me 均可抑制肿瘤向远处器官的转移。CDDO-Me 治疗可抑制前列腺中生存相关的 p-Akt 和 NF-κB 的表达，在 TRAMPC-1 肿瘤细胞中敲低 Akt 可使它们对 CDDO-Me 敏感。这些发现表明 Akt 是体外 TRAMPC-1 细胞中细胞凋亡的靶标，并且可能是 CDDO-Me 抑制体内前列腺癌的靶标。
