The chemopreventive flavonoid apigenin induces G₂/M arrest in keratinocytes

Abstract

Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically, and may represent an alternative sunscreen agent in humans. We have investigated the molecular mechanism(s) by which apigenin inhibits skin tumorigenesis. Initial studies examined the effects of apigenin on the cell cycle. DNA flow cytometric analysis indicated that culturing cells for 24 h in medium containing apigenin induced a G2/M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G2/M arrest was fully reversible after an additional 24 h in medium without apigenin. We investigated the effects of apigenin on cyclin B1 and p34cdc2, since cyclin B1/p34cdc2 complexes regulate G2/M progression. Western blot and immune complex kinase assays using whole cell lysates from 308 and C50 cells treated for 24 h with 0-70 microM doses of apigenin demonstrated that apigenin treatment did not change the steady-state level of p34cdc2 protein, but did inhibit p34cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclin B1 protein in a dose-dependent manner. The apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of apigenin. In conclusion, we present evidence that apigenin induces a reversible G2/M arrest in cultured keratinocytes, the mechanism of which is in part due to inhibition of the mitotic kinase activity of p34cd2, and perturbation of cyclin B1 levels.

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

“…The flavone-induced G 2 -M arrest apparent in breast cancer cells in the present study was likely mediated by p21 Waf1 , which induces such arrest in a variety of cell types [33,34,35,36]. In contrast to its effects in malignant cells, flavone induced G 0 -G 1 arrest without apoptosis in nonmalignant breast epithelial cells, suggesting that nonmalignant cells might be able to regain their proliferative capacity.…”

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

“…Because of its potential antioxidant, anti-inflammatory, and anti-tumor properties, apigenin is a candidate cancer chemopreventive agent (Birt et al, 1997;Birt et al, 1996;Lepley et al, 1996;Ross and Kasum, 2002). Apigenin treatment inhibits cell proliferation in cancer cell types (Sarkar and Li, 2004).…”

In vitro Cytotoxic Activity of Salsola oppositifolia Desf. (Amaranthaceae) in a Panel of Tumour Cell Lines

“…Moreover, flavonoids exert specific cytotoxic activity towards cancer cells which has generated large interest in devel-0939Ð5075/2008/0500Ð0347 $ 06.00 " 2008 Verlag der Zeitschrift für Naturforschung, Tübingen · http://www.znaturforsch.com · D oping flavonoid-based cytostatics for anticancer therapy (Galati and O'Brien, 2004). Different mechanisms are linked to flavonoid-mediated cytotoxicity, including proteasome inhibition (Chen et al, 2005), inhibition of fatty acid synthesis (Brusselmans et al, 2005), topoisomerase inhibition (Constantinou et al, 1995), inhibition of phosphatidyl-inositol 3-kinase (Agullo et al, 1997), induction of cell cycle arrest (Lepley et al, 1996), induction of p53 (Plaumann et al, 1996) or enhanced expression of c-fos and c-myc proto-oncogenes (Chen et al, 1998).…”