Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells.
Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells.
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发表时间：
2010-03
影响因子：
2
通讯作者：
Xiaohua Gao;D. Deeb;J. Hao;Yongbo Liu;A. Arbab;S. Dulchavsky;S. Gautam
中科院分区：
文献类型：
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作者：
Xiaohua Gao;D. Deeb;J. Hao;Yongbo Liu;A. Arbab;S. Dulchavsky;S. Gautam
缺乏凋亡细胞死亡与恶性转化和对抗癌治疗的抵抗有关。促进肿瘤细胞凋亡可能导致难治性结直肠癌的消退和预后改善。合成的三萜类化合物对多种类型的癌细胞显示出较强的抗肿瘤活性，但尚未对结直肠癌进行研究。本研究检测了齐墩烷三萜2-氰-3,12-二氧齐墩烷-1,9(11)-二烯-28-酸（CDDO）及其C-28甲酯（CDDO- me）和C-28咪唑（CDDO- im）衍生物对结直肠癌细胞株的诱导凋亡活性。细胞生长/活力测定（MTS）表明，结肠直肠癌细胞对浓度为1.25 ~ 10微米的CDDO-Me高度敏感。PARP-1的裂解、原胞浆酶-3、-8和-9的激活以及线粒体去极化表明，肿瘤细胞的主要破坏模式是凋亡。CDDO-Me诱导细胞凋亡与抑制促存活Akt、NF-kappaB和mTOR信号蛋白以及NF-kappaB调控的抗凋亡蛋白Bcl-2、Bcl-xL、Bad和survivin有关。这些研究为CDDO-Me治疗晚期化疗难治性结直肠癌的临床评价提供了依据。
Lack of apoptotic cell death has been implicated in malignant transformation and resistance to anticancer therapies. The promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of refractory colorectal cancer. Synthetic triterpenoids have shown strong antitumorigenic activity towards diverse cancer cell types, but have not been investigated for colorectal cancer. In the present study, we tested the apoptosis-inducing activity of oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives in colorectal cancer cells lines. Cell growth/viability assay (MTS) demonstrated that colorectal cancer cells are highly sensitive to CDDO-Me at concentrations of 1.25 to 10 microM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization. Induction of apoptosis by CDDO-Me was associated with the inhibition of pro-survival Akt, NF-kappaB and mTOR signaling proteins and NF-kappaB-regulated anti-apoptotic Bcl-2, Bcl-xL, Bad and survivin. These studies provide rationale for clinical evaluation of CDDO-Me for the treatment of advanced chemotherapy refractory colorectal cancer.