Hung Mei-Whey, Shiao Ming-Shi, Tsai Lai-Chen, Chang Gu-Gang, Chang Tsu-Chung
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
Anticancer Res. 2003 Nov-Dec;23(6C):4773-80.
Caffeic acid phenylether ester (CAPE) has potent antioxidant, anti-inflammatory, antiviral, anti-proliferative, immunomodulatory and pro-apoptotic activities. The activities of CAPE and its novel synthetic derivatives, caffeic acid octyl ester (CAO) and 1-octyl caffeamide (CAN-8), were investigated in this study.
Cultured human cells were incubated with or without these compounds. The effect of these compounds on cell apoptosis, intracellular level of hydrogen peroxide and mitochondrial potential were analyzed. Western blot analysis was used to study the effect of alterations in protein level of caspases, Bcl-2 family, p21, p53 and c-Jun upon drug treatment.
These compounds arrested cell proliferation, triggered cell apoptosis and caused a marked scavenging effect of hydrogen peroxide. Apoptosis induced by CAPE or CAO is associated with increased expression of p53, p21 and c-Jun. While the levels of Bcl-2 and Bcl-xL were relatively unchanged, these compounds induced a marked reduction in Mcl-1 level. The CAPE- or CAO-induced apoptosis was also accompanied by a rapid loss of mitochondrial transmembrane potential and activation of caspase-3 and caspase-8, suggesting a mitochondrial-dependent mechanism. In causing these cellular actions, CAO was shown to be comparable or more potent than CAPE, whereas the amide analogue CAN-8 displayed much weaker activities than both CAPE and CAO. Since these three compounds contain similar antioxidant functionality, the difference in their potency suggests that the octyl moiety in CAO is an important determinant for the enhanced activities.
We have characterized a novel CAPE structure analogue, CAO, which showed strong antioxidant and proapoptotic activities. In addition, we demonstrated that down-regulation of Mcl-1 gene expression and activation of caspase-8 are associated with CAPE-triggered cell apoptosis.
咖啡酸苯乙酯（CAPE）具有强大的抗氧化、抗炎、抗病毒、抗增殖、免疫调节和促凋亡活性。本研究对CAPE及其新型合成衍生物咖啡酸辛酯（CAO）和1-辛基咖啡酰胺（CAN-8）的活性进行了研究。
将培养的人类细胞与这些化合物一起或不与这些化合物一起孵育。分析了这些化合物对细胞凋亡、细胞内过氧化氢水平和线粒体电位的影响。采用蛋白质印迹分析研究药物处理后半胱天冬酶、Bcl-2家族、p21、p53和c-Jun蛋白水平变化的影响。
这些化合物抑制细胞增殖，引发细胞凋亡，并对过氧化氢产生显著的清除作用。CAPE或CAO诱导的凋亡与p53、p21和c-Jun表达增加有关。虽然Bcl-2和Bcl-xL水平相对未变，但这些化合物导致Mcl-1水平显著降低。CAPE或CAO诱导的凋亡还伴随着线粒体跨膜电位的快速丧失以及半胱天冬酶-3和半胱天冬酶-8的激活，提示存在线粒体依赖性机制。在引起这些细胞作用方面，CAO显示出与CAPE相当或更强的效力，而酰胺类似物CAN-8的活性比CAPE和CAO都弱得多。由于这三种化合物具有相似的抗氧化功能，它们效力的差异表明CAO中的辛基部分是增强活性的重要决定因素。
我们鉴定了一种新型的CAPE结构类似物CAO，其具有强大的抗氧化和促凋亡活性。此外，我们证明Mcl-1基因表达的下调和半胱天冬酶-8的激活与CAPE触发的细胞凋亡有关。
