Synthetic triterpenoid cyano enone of methyl boswellate activates intrinsic, extrinsic, and endoplasmic reticulum stress cell death pathways in tumor cell lines.
Synthetic triterpenoid cyano enone of methyl boswellate activates intrinsic, extrinsic, and endoplasmic reticulum stress cell death pathways in tumor cell lines.
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DOI：
10.1158/1535-7163.mct-10-0887
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发表时间：
2011-09
影响因子：
5.7
通讯作者：
Reed JC
中科院分区：
文献类型：
--
作者：
Ravanan P;Sano R;Talwar P;Ogasawara S;Matsuzawa S;Cuddy M;Singh SK;Rao GS;Kondaiah P;Reed JC
我们探索了一种新的合成三萜化合物乳香酸甲酯氰基烯酮（CEMB）对各种前列腺癌和神经胶质瘤癌细胞系的作用。CEMB显示浓度依赖性细胞毒活性，在10个测试的肿瘤细胞系中具有亚微摩尔半数致死剂量（LD 50）值。CEMB诱导的细胞毒性伴随着下游效应物半胱天冬酶（半胱天冬酶3和7）的活化以及参与外源性（半胱天冬酶8）和内源性（半胱天冬酶9）凋亡途径的上游引发物半胱天冬酶。通过使用小干扰RNA（siRNA），我们证明了caspase 8、死亡受体4（DR 4）、Apaf-1和Bid的敲低损害CEMB诱导的细胞死亡的证据。与其他促凋亡合成三萜类化合物类似，CEMB诱导的凋亡涉及内质网（ER）应激，如通过siRNA介导的参与未折叠蛋白应答的基因（如Ire 1、Perk和ATF 6）表达的敲低部分拯救肿瘤细胞所证明的。总之，我们的研究结果表明，CEMB刺激癌细胞中的几个凋亡途径，这表明该化合物应进一步评估作为一种潜在的癌症治疗药物。
We explored the effect of a novel synthetic triterpenoid compound Cyano Enone of Methyl Boswellates (CEMB) on various prostate cancer and glioma cancer cell lines. CEMB displayed concentration-dependent cytotoxic activity with submicromolar lethal dose 50% (LD50) values in ten of ten tumor cell lines tested. CEMB-induced cytotoxicity is accompanied by activation of downstream effector caspases (caspases 3 and 7) and by upstream initiator caspases involved in both the extrinsic (caspase 8) and intrinsic (caspase 9) apoptotic pathways. By using small interfering RNAs (siRNAs), we show evidence that knock down of caspase 8, death receptor 4 (DR4), Apaf-1, and Bid impairs CEMB-induced cell death. Similar to other proapoptotic synthetic triterpenoid compounds, CEMB-induced apoptosis involved endoplasmic reticulum (ER) stress, as demonstrated by partial rescue of tumor cells by siRNA-mediated knock-down of expression of genes involve in the unfolded protein response such as Ire1, Perk, and ATF6. Altogether our results suggest that CEMB stimulates several apoptotic pathways in cancer cells, suggesting that this compound should be evaluated further as a potential agent for cancer therapy.