Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

Abstract

The promotion stage in the multistep process of epidermal tumorigenesis is NF-kB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated whether the NF-kB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-kB target genes, p21 and cyclin D1.Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6Pþ 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-kB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NFkB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-kB 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 p21À/À 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 JB6Pþ 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/NFkB, 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. Cancer Prev Res; 5(11); 1298-309. Ó2012 AACR.

Synthesis, Characterization, Anticancer, and Antioxidant Studies of Ru(III) Complexes of Monobasic Tridentate Schiff Bases

“…Figures 2 –4 represent the cell viability percentages of ruthenium(III)-Schiff base complexes and parthenolide drug against TK-10, UACC-62, and MCF-7 cell lines, at different concentrations of ruthenium(III) compounds or parthenolide. A high level of antiproliferative potentials against the studied cell lines was exhibited by parthenolide in accordance with earlier reports [45]. The obtained results revealed that treatment of cell lines with different concentrations of Ru(III)-Schiff base complexes efficiently affected cell viability towards MCF-7 cells, as displayed in Figures 2 –4 and Table 1.…”

Synthesis, characterization, andin vitroantioxidant and anticancer studies of ruthenium(III) complexes of symmetric and asymmetric tetradentate Schiff bases

“…Parthenolide demonstrated high levels of antiproliferative effect against all cell lines, in accord with previous reports [70]. The values of the concentration of the compounds for 50% inhibition (IC 50 ) were obtained from non-linear regression analysis of dose response data for the compounds tested and are presented in 5), which is in agreement to their order of in vitro DPPH scavenging ability of the Ru(III) complexes.…”

Dissecting the role of the tubulin code in mitosis

“…The sesquiterpene lactones Parthenolide and Costunolide were originally identified as inhibitors of the NF-κB pathway (Bork, Schmitz, Kuhnt, Escher, & Heinrich, 1997), but their roles in modulating the tyrosination-detyrosination cycle have also recently been described (Barisic & Maiato, 2016; Fonrose et al, 2007; Whipple et al, 2013). In the case of Parthenolide, it has notable anticancer properties and its activity has been linked to several cellular processes including apoptosis (Gopal, Arora, & Van Dyke, 2007), DNA methylation (Liu et al, 2009), p21 signalling (Ghantous et al, 2012) and the regulation of TNF-α (Zhang et al, 2017), amongst others. Since Parthenolide has highly reactive groups that confer high levels of non-specificity, its careful use at the correct dose, as well as proper storage and avoidance of freeze-thaw cycles is highly recommended.…”