Ursolic acid
Ursolic acid (3beta-hydroxy-urs-12-en-28-oic acid) is a pentacyclic triterpenoid found naturally in apples, waxy berries, rosemary, oregano, and several other plants and herbs used in medicine and the diet.1,2 It is known to have significant antioxidant, anti-inflammatory, and antiproliferative properties, and has also been associated with a wider range of biologic activities, including anticancer, antimicrobial, antitumor, antiwrinkle, anti-HIV, cytotoxic, and hepatoprotective.3,4 In addition, ursolic acid is the focus of human clinical trials for potential uses in cancer and skin wrinkles.4 While this triterpenoid is known to suppress tumor formation and viability in various kinds of cancer, including skin cancer, several forms of cancer are resistant to ursolic acid.
Anti-inflammatory activity
In a 2013 study of the antibacterial and anti-inflammatory effects of Syzygium jambos on acne, Sharma et al. found that ursolic acid was one of the constituents of the leaf extracts that contributed to a significant suppression of the release of inflammatory cytokines interleukin (IL)-8 and tumor necrosis factor-alpha.5
In 2010, Yang et al. identified ursolic acid as a key constituent of Acanthopanax koreanum fruit, a popular fruit in Jeju Island, South Korea, extracts of which they found to exhibit significant anti-inflammatory activity and suitability as a topical agent.6
,Yasukawa et al. conducted an in vivo two-stage carcinogenesis test in mice in 2009 in which extracts of the branches of Hippophae rhamnoides displayed significant antitumor activity after initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Ursolic acid and (-)-epigallocatechin were the constituents found to have the greatest inhibitory effects on TPA-induced inflammation.7
A 2002 study by Chattopadhyay et al. revealed that the ursolic acid present in Mallotus peltatus extract (long used in traditional folk medicine to treat skin infections and intestinal disorders) may partially account for the broad anti-inflammatory and antimicrobial activity of the plant.9
In 1997, Máñez et al. noted that ursolic acid was among two of the four selected natural triterpenoids tested and found to be significantly effective against inflammation in a TPA multiple-dose model of chronic skin inflammation.10
Anticancer activity
In 2015, Cho et al. reported on the inhibitory effects on skin tumor promotion from the topical application of ursolic acid, resveratrol, or the combination of the two prior to TPA treatment on mouse skin. The combination of the two botanical agents yielded the strongest suppression of TPA-induced epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion.11
In another study that year buttressing the combination of the two botanical agents, Junco et al. demonstrated that chloroquine could be used to sensitize B16F10 metastatic mouse melanoma to the anticancer activities of ursolic acid and resveratrol. The investigators concluded that the combination of ursolic acid or resveratrol with chloroquine has potential for inclusion in melanoma treatment in humans.12 Previously, Junco et al. observed that the anti–skin cancer effects of ursolic acid are augmented by P-glycoprotein inhibitors, and that ursolic acid and the stilbene resveratrol, a potent antioxidant, work synergistically, although not by blocking P-glycoprotein. The investigators suggested that ursolic acid along with resveratrol and/or P-glycoprotein inhibitors have potential as effective anti–skin cancer regimens.
In 2014, Lee et al. showed that ursolic acid can differentially modulate apoptosis in cutaneous melanoma and retinal pigment epithelial cells exposed to ultraviolet to visible broadband radiation, exhibiting the potential to protect normal cells while sensitizing melanoma cells to the effects of UV radiation.13 These findings supported earlier work by the team showing that pretreatment of human cells derived from a malignant skin melanoma markedly enhanced the sensitivity of melanoma cells to UV radiation, while providing some photoprotection to retinal pigment epithelium.
Also that year, Soica et al. demonstrated, using in vitro tests and in vivo skin cancer models, that the mixture of oleanolic and ursolic acids and in complex with cyclodextrin rendered a synergistic antitumor activity.14
A year earlier, Kowalczyk et al. showed that the combined action of phytochemicals – dietary calcium D-glucarate and topical ursolic acid and resveratrol – was effective in suppressing the initiation (with 7,12-dimethylbenz[a]anthracene [DMBA]) and promotion (with TPA) of skin tumorigenesis in SENCAR mice. Ursolic acid alone or in combination with calcium D-glucarate significantly diminished epidermal hyperplasia when applied during promotion. All of the antipromotion protocols led to significant decreases in cyclooxygenase-2 and interleukin (IL)-6 expression. The researchers concluded that ursolic acid strongly inhibits skin tumor promotion and inflammatory signaling, and warrants attention as a potential preventive agent against skin and other epithelial cancers.15 Kowalczyk et al. had previously found that ursolic acid and other phytochemicals displayed significant in vitro and in vivo antioxidant and antitumorigenic activity, inhibiting murine skin carcinogenesis by blunting tumor initiation and tumor promotion/progression.16
In 2006, beta-ursolic acid isolated from Salvia officinalis was found by Jedinák et al. to be effective in suppressing lung colonization of beta16 mouse melanoma cells in vivo.17
Huang et al. showed in 1994 that extracts of the leaves of Rosmarinus officinalis (rosemary) were effective in suppressing tumor initiation and promotion in a two-stage skin tumorigenesis mouse model. Topically applied ursolic acid isolated from the leaves was found to hinder TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. The number of tumors per mouse also declined significantly due to the topical application of ursolic acid concurrent with twice weekly application of the tumor-promoter TPA in DMBA-initiated mice.18
