Evaluation of pentacyclic triterpenes found inPerilla frutescensfor inhibition of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate

Abstract

A series of pentacyclic tritperpenes found in Perilla frutescens (P. frutescens), including ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on epidermal cell signaling, proliferation, and skin inflammation in relation to their ability to inhibit skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) and compared to UA as the prototype compound. All compounds were given topically 30 min prior to each TPA application and significantly inhibited skin tumor promotion. 3-epiCA and MA were significantly more effective than UA at inhibiting tumor development. All of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds also reduced skin inflammation (assessed by infiltration of mast cells and T-cells) and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were again more effective than UA. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation (i.e., phosphorylation) of IGF-1R, STAT3 and Src. Further study of these compounds, especially 3-epiCA and MA, for chemopreventive activity in other cancer model systems is warranted.

Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism

“…Betulinic acid, caffeic acid phenylethyl ester, genistein, palmatine chloride, shikonin and RES were purchased from CaymanChemicals (Ann Arbor, MI, USA), whereas >98% pure corosolic acid, epi-maslinic acid, epi-UA, epi-corosolic and maslinic acid were prepared as recently described. 58 , 59 For all screens, cells in exponential proliferation were seeded in 384-well plates using a Viaflo Assist micro-plate dispenser (Integra Biosciences, Hudson, NH, USA) and allowed to adhere overnight. During the primary screening, HMVP2 cells were screened with the individual NCL compounds at 3 time-points (12, 24 or 48 h) and three doses (5, 10, 20 µM final concentration).…”

Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin

“…Furthermore, UA and Curc both reduced mRNA levels of Cox‐2, a transcriptional target of NF‐κB. Using a higher dose of 2 μmol, we previously reported that UA inhibited TPA‐induced upregluation of Cox‐2 protein levels, and others have shown that Curc also inhibits TPA‐induced protein levels of Cox‐2 . Thus, the greater effects of the combination of UA + Curc on this signaling pathway likely contributed to the greater effects seen on tumor promotion as well as on inflammatory gene expression.…”

“…B, Quantitation of Western blots (mean ± SEM; average of at least three independent experiments). *, Significant when compared to TPA group; †, Significant when compared to UA + TPA; #, Significant when compared to Curc + TPA; (P ≤ 0.05, Mann-Whitney U test) we previously reported that UA inhibited TPA-induced upregluation of Cox-2 protein levels, and others have shown that Curc also inhibits TPA-induced protein levels of Cox-2 8. 22 Thus, the greater effects of the combination of UA + Curc on this signaling pathway likely contributed to the greater effects seen on tumor promotion as well as on inflammatory gene expression.…”

“…[3][4][5][6] Urolic acid (UA) and curcumin (Curc) are two examples of phytochemicals that have been shown to inhibit tumor development as single agents in a two-stage skin carcinogenesis model, especially during the tumor promotion stage. [7][8][9] UA is a pentacyclic triterpenoid found in plants and herbs such as Perilla frutescens (Japanese basil), rosemary, cranberries, and the peels of apples. 10,11 UA has been shown to possess many beneficial cancer prevention properties including anti-inflammatory, antioxidant, and anti-proliferative activities.…”

Role of AMPK and PPARα in the anti‐skin cancer effects of ursolic acid

“…Recent studies from our laboratories using an in vivo model of skin tumor promotion have shown that UA and related triterpenes given topically can activate AMPK in the epidermis of mice treated with TPA . AMPK activation correlated with increased phosphorylation of ULK1 (Ser555) suggesting that AMPK activation by UA and related triterpenes may lead to induction of autophagic cell death.…”