Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention

Abstract

The purpose of our study was to investigate in vitro the potential cancer preventive properties of several phytochemicals, i.e. grape seed extract (GSE), resveratrol (RES), ursolic acid (URA), ellagic acid (ELA), lycopene and N-acetyl-L-cysteine (NAC) to define the mechanisms by which these compounds may inhibit murine skin carcinogenesis. We measured quenching of peroxyl, superoxide and hydroxyl radicals by these phytochemicals. We also used adenosine triphosphate (ATP) bioluminescence, Caspase-Glo 3/7 and P450-Glo (CYP1A1 and CYP1B1) assays to study antiproliferative, proapoptotic and CYP-inhibiting effects of the phytochemicals. We next determined their effects on a 4 week inflammatory hyperplasia assay using 7,12-dimethylbenz[a]anthracene-induced murine skin carcinogenesis model to further understand their mechanism of action. Three murine keratinocyte cell lines, i.e. non-tumorigenic (3PC), papilloma-derived (MT1/2) and squamous cell carcinoma-derived (Ca3/7) cell lines, were used in in vitro assays. We have found that GSE, ELA and RES are potent scavengers of peroxyl and superoxide radicals. Statistically significant effects on activities of caspase-3 and -7 were observed only after GSE and URA treatments. All tested compounds protected cells from hydrogen peroxide-induced DNA damage. Using a short-term complete carcinogenesis assay, we have found that all selected compounds caused marked decreases of epidermal thickness and (except RES) reduced percentages of mice with mutation in codon 61 of Ha-ras oncogene. In conclusion, differential effects of tested phytochemicals on events and processes critical for the growth inhibition of keratinocytes in vitro and in vivo indicate that combinations of tested compounds may, in the future, better counteract both tumor initiation and tumor promotion/progression.

Ursolic Acid, a Pentacyclin Triterpene, Potentiates TRAIL-induced Apoptosis through p53-independent Up-regulation of Death Receptors

“…8), thus rendering cancer cells more sensitive to the cytotoxic activities of TRAIL. Considering that UA by itself is highly safe and exhibits anticancer activities against a wide variety of tumors in vitro (12,13,18) and in vivo (22,63), its potential use in combination with TRAIL should be explored. Further studies in animals are needed to investigate the anticancer potential of UA in combination with TRAIL.…”

Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells

“…Previous studies have shown that UA is effective against various types of cancer both in vitro and in vivo. 16,17 Purported mechanisms include cell cycle arrest and apoptosis induction through inhibition of AKT, 18 STAT3, 19 NFKB1 20 and activation of MAPK8/9/10 21 or TP53 22 signaling pathways. However, the role of ER stress response in UA-induced apoptosis has not been addressed.…”

p21 induction plays a dual role in anti-cancer activity of ursolic acid

“…It has been shown that UA is effective against various types of cancer both in vitro and in vivo. 11,12 The induction of G1 cell cycle arrest and apoptosis by UA has been suggested to contribute to its anti-cancer activities. [13][14][15][16] Previous studies have shown that induction of G1 arrest and apoptosis by UA is associated with up-regulation of cyclin-dependent kinase inhibitor (CDKI) protein p21Cip1 in multiple types of cancer cells.…”