title: Caffeic acid phenethyl ester (CAPE) prevents transformation of human cells by arsenite (As) and suppresses growth of As-transformed cells.
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.
authors.affiliation: Department of Environmental Medicine and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. cfyang@spirit.gcrc.upenn.edu
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Ronghe
authors.initials: R
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Eckard
authors.forename: Rita
authors.initials: R
authors.lastname: Yusuf
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.forename: Toby G
authors.initials: TG
authors.lastname: Rossman
authors.forename: Krystyna
authors.initials: K
authors.lastname: Frenkel
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002109:Caffeic Acids / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D005434:Flow Cytometry; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000139:chemically induced / Q000473:pathology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D018053:Arsenites; D002109:Caffeic Acids; D016207:Cytokines; D012333:RNA, Messenger; D013267:Stilbenes; D002392:Catechin; C055494:caffeic acid phenethyl ester; C057580:gallocatechol; D010626:Phenylethyl Alcohol; C015001:arsenite; D000077185:Resveratrol