Apoptotic effect of caffeic acid phenethyl ester and its ester and amide analogues in human cervical cancer ME180 cells.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hung
Mei-Whey
MW
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
Shiao
Ming-Shi
MS
Tsai
Lai-Chen
LC
Chang
Gu-Gang
GG
Chang
Tsu-Chung
TC
D000577:Amides / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002109:Caffeic Acids / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D003603:Cytotoxins / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007700:Kinetics; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms
D000577:Amides; D002109:Caffeic Acids; D003603:Cytotoxins; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol