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
Ursolic acid isolated from ethanol extracts of the leaves of Perilla frutescens (red perilla) also was demonstrated by Banno et al. in 2004 to exhibit anti-inflammatory activity as well as strong inhibitory effects against the Epstein-Barr virus early antigen in mice.8
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
Antiaging and other activities
In 2015, Herndon et al. conducted an open-label clinical trial in 37 females (aged 35-60 years) to ascertain the effectiveness of an anti-aging moisturizer containing Astragalus membranaceus root extract, a peptide blend including palmitoyl tripeptide-38, standardized rosemary leaf extract (ursolic acid), tetrahexyldecyl ascorbate (THD ascorbate), and ubiquinone (coenzyme Q10). Subjects were instructed to apply the moisturizer once in the morning and once in the evening, and were assessed at baseline, and after 4, 8, and 12 weeks of twice daily application. Clinical evaluations after 8 weeks revealed a statistically significant improvement in all grading parameters (fine lines and wrinkles, clarity/brightness, visual roughness, tactile roughness, redness, hyperpigmentation, and overall appearance), with even more pronounced improvement at 12 weeks. The product was found to be mild and well tolerated, and digital photography reinforced clinical assessments and self-evaluations.19
Lee et al. reported in 2012 on in vitro results suggesting that ursolic acid was effective as an inhibitor of matrix metalloproteinase (MMP)-1 after UVB exposure and was more effective than retinoic acid.20
Based on studies with hairless mice, Lim et al. found in 2007 that ursolic and oleanolic acids can enhance the recovery of skin barrier function and, via peroxisome proliferator-activated receptor-alpha, spur epidermal keratinocyte differentiation. They concluded that both acids have potential for use as agents to promote epidermal permeability barrier function.21
In 2003, Soo et al. observed that pretreatment with ursolic acid inhibited UVA-induced oxidative stress and activation and expression of MMP-2 in HaCaT human keratinocytes. They concluded that ursolic acid may merit attention for the prevention of UVA-induced photoaging.22
Three years earlier, Yarosh et al. showed that liposomes containing ursolic acid augmented ceramide content in cultured normal human epidermal keratinocytes and collagen content in cultured normal human dermal fibroblasts. Over an 11-day period, clinical tests with the ursolic acid–containing liposome (Merotaine) revealed increases in the ceramide content in human skin.23 Two years later, many of the same researchers duplicated their results. This new study also demonstrated that ursolic acid liposomes raise ceramide levels in normal human epidermal keratinocytes, in contrast to the effects of retinoic acid, earlier shown to reduce such levels. They concluded that ursolic acid liposomes show promise for use alone or in combination to replenish or maintain cutaneous ceramide and collagen levels.24 Notably, ursolic acid is incorporated into topical oils and creams intended to confer rejuvenating effects to the skin.
Conclusion
Ursolic acid is a compelling ingredient. I especially will be interested in the results of ongoing human clinical trials of this triterpenoid for treating cancer and skin wrinkles. As it is, ursolic acid is known to exert significant inhibitory activity against tumor formation and tumor cell viability in the laboratory. Given its wide range of biologic activity, and some promising cutaneous results, there is reason to believe that ursolic acid has the potential to play an increasingly useful role in topical skin care agents and dermatologic practice.
References
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Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. Dr. Baumann also developed and owns the Baumann Skin Type Solution skin typing systems and related products.
