Title: Caffeic acid phenethyl ester (CAPE) prevents transformation of human cells by arsenite (As) and suppresses growth of As-transformed cells.
Authors: Yang, Chengfeng; Wu, Jing; Zhang, Ronghe; Zhang, Ping; Eckard, Jonathan; Yusuf, Rita; Huang, Xi; Rossman, Toby G; Frenkel, Krystyna
Published In Toxicology, (2005 Sep 15)
Abstract: Recent evidence suggests that inflammatory cytokines and growth factors contribute to arsenite (As)-induced human carcinogenesis. We investigated the expression of inflammatory cytokine mRNAs during the transformation process induced by chronic As exposure in non-tumorigenic human osteogenic sarcoma (N-HOS) cells using gene arrays, and results were confirmed by RT-PCR and protein arrays. Caffeic acid phenethyl ester (CAPE), a naturally occurring immunomodulating agent, was used to evaluate the role of inflammatory factors in the process of As-mediated N-HOS cell transformation and in As-transformed HOS (AsT-HOS) cells. We found that an 8-week continuous exposure of N-HOS to 0.3 microM arsenite resulted in HOS cell transformation. That exposure also caused substantial decreases in inflammatory cytokine mRNAs, such as interleukin (IL) IL-1alpha, IL-2, IL-8, IL-18, MCP-1, TGF-beta2, and TNF-alpha, while it increased c-jun mRNA in a time-dependent manner. Co-incubation of N-HOS with As and CAPE (0.5-2.5 microM) prevented As-mediated declines in cytokine mRNAs in the co-treated cells, as well as their transformation to anchorage independence, while it caused decreases in c-jun mRNA. CAPE (up to 10 microM) had no effect on growth of N-HOS cells. However, CAPE (1-10 microM) treatment of AsT-HOS cells inhibited cell growth, induced cell cycle G2/M arrest, and triggered apoptosis, accompanied by changes in cytokine gene expression, as well as decreases in cyclin B1 and cdc2 abundance. Resveratrol (RV) and (-)(.) epigallocatechin gallate (EGCG), preventive agents present in grapes and green tea, respectively, induced similar changes in AsT-HOS cell growth but required much higher doses than CAPE to cause 50% growth arrest (<2.5 microM CAPE versus 25 microM RV or 50 microM EGCG). Overall, our findings suggest that inflammatory cytokines play an important role in the suppressive effects of CAPE on As-induced cell transformation and in the selective cytotoxicity of CAPE to As-transformed HOS cells.
PubMed ID: 16085347
MeSH Terms: Antioxidants/pharmacology*; Apoptosis/drug effects*; Arsenites/antagonists & inhibitors*; Arsenites/toxicity*; Caffeic Acids/pharmacology*; Catechin/analogs & derivatives; Catechin/pharmacology; Cell Growth Processes/drug effects; Cell Line; Cell Survival/drug effects; Cell Transformation, Neoplastic/drug effects*; Cell Transformation, Neoplastic/metabolism; Cytokines/biosynthesis; Cytokines/genetics; Drug Interactions; Flow Cytometry; Humans; Oligonucleotide Array Sequence Analysis; Osteosarcoma/chemically induced; Osteosarcoma/pathology; Phenylethyl Alcohol/analogs & derivatives*; Phenylethyl Alcohol/pharmacology; RNA, Messenger/biosynthesis; RNA, Messenger/genetics; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes/pharmacology