title: Inhibition of tumor promotion by parthenolide: epigenetic modulation of p21.
abstract: The promotion stage in the multistep process of epidermal tumorigenesis is NF-кB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-кB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-кB target genes, p21 and cyclin D1. Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6P+ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-кB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NF-кB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-кB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21 -/- cancer cells and showed that the loss of p21 is cytoprotective against parthenolide. Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6P+ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NF-кB, whereas it increased p21 expression. These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy.
authors.affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon.
authors.forename: Akram
authors.initials: A
authors.lastname: Ghantous
authors.forename: Melody
authors.initials: M
authors.lastname: Saikali
authors.forename: Tilman
authors.initials: T
authors.lastname: Rau
authors.forename: Hala
authors.initials: H
authors.lastname: Gali-Muhtasib
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Nadine
authors.initials: N
authors.lastname: Darwiche
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics / Q000517:prevention & control*; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012717:Sesquiterpenes; C002669:parthenolide