Chemopreventive Effects of Licorice and Its Components
Curr Pharmacol Rep (2015) 1:60–71
DOI 10.1007/s40495-014-0015-5
CANCER CHEMOPREVENTION (R AGARWAL, SECTION EDITOR)
Chemopreventive Effects of Licorice and Its Components
Ann M. Bode & Zigang Dong
Published online: 28 January 2015
# Springer International Publishing AG 2015
Abstract Cancer is still a major health issue worldwide and
identifying novel but safe compounds for prevention and
treatment is a high priority. Licorice (Glycyrrhiza) is a perennial plant that is cultivated in many countries and has been
reported to exert antioxidant, anti-inflammatory and anticancer effects. However, some components of licorice exert unwanted side effects and therefore identifying safer licorice
components would be ideal. The anticancer activities of many
of the licorice components appear to include cycle arrest,
apoptosis induction, and general antioxidant effects. Commonly reported indirect protein targets important in tumorigenesis include many cell cycle-related proteins, apoptosisassociated proteins, MMP proteins, COX-2, GSK-β, Akt,
NF-κB, and MAP kinases. Importantly, several licorice components were reported to directly bind to and inhibit the
activities of PI3-K, MKK4, MKK7, JNK1, mTOR, and
Cdk2, resulting in decreased carcinogenesis in several cell
and mouse models with no obvious toxicity. This review
focuses on specific components of licorice for which a direct
protein target has been identified.
Keywords Glycyrrhizic acid . Glycyrrhetic acid .
Iso-liquiritigenin . Isoangustone A . Licochalcone A .
Licochalcone E
This article is part of the Topical Collection on Cancer Chemoprevention
A. M. Bode (*) : Z. Dong
The Hormel Institute University of Minnesota, 801 16th Ave NE,
Austin, MN 55912, USA
e-mail:
Z. Dong
e-mail:
Introduction
Despite efforts and advances in prevention and treatment,
cancer is still a major cause of death in most countries. Cancer
is a worldwide health threat with major physical, social, and
economic burdens. Because cancer is believed to be preventable, attention has centered on dietary phytochemicals and
natural compounds as effective interventions in cancer development. However, the failure of many large-scale clinical
trials has questioned whether diet-based cancer prevention or
therapy can succeed. Two major weaknesses plagued many of
these trials: (1) a lack of mechanism-based preclinical studies
to support the trial; and (2) a lack of knowledge regarding the
specific molecular or cellular targets of the selected dietary
agents or functional foods. One of the greatest challenges for
researchers is to reduce the accumulation of distortion and
half-truths reported in the popular media regarding the health
benefits of certain foods or food supplements. The use of these
substances is not new, but interest has increased dramatically
because of perceived health benefits presumably acquired
without unpleasant side effects. However, the effects of
long-term consumption of food supplements and specific
dietary factors have not been extensively studied.
Many anticancer drugs exert adverse side effects, which
can be severe or deadly. Thus, identification of novel anticancer compounds from natural products was proposed as a safer
alternative and a promising strategy for cancer prevention or
treatment. Many traditional herbal medicines and certain food
constituents exhibit anti-inflammatory and antioxidant effects,
suggesting their potential as chemopreventive or therapeutic
agents. Licorice (Glycyrrhiza) is a perennial plant that is
cultivated in several countries, including China, Russia,
Spain, Persia, and India. Licorice extract from the root is very
sweet and is a common source of licorice used in traditional
and herbal medicines [1]. Licorice is one of the oldest referenced botanicals with a written record referring to the use of
Curr Pharmacol Rep (2015) 1:60–71
licorice dated 2100 BC [2]. Notably, about 90 % of the licorice
produced is used as a flavoring agent for tobacco products,
such as American blend cigarettes, moist snuff, chewing tobacco, and pipe tobacco [3]. Licorice flavoring is added to
candies, chewing gum, soft drinks (e.g., root beer) and other
beverages (e.g., herbal teas), toothpaste, and herbal remedies
for cough and stomach problems and the overconsumption of
these products is associated with increased risk of licorice
intoxication [4]. Licorice is consumed worldwide and estimates suggest an annual consumption of about 1.5 kg/person
[5], with some individuals consuming as much as 100 g of
licorice per week [6]. Glycyrrhetic acid from licorice is associated with hypertension [7]. Consuming as little as 50 g or
2 oz of licorice, which contain about 75 mg glycyrrhetic acid,
daily over a 2-week-period reportedly caused a significant
increase in blood pressure [8].
In contrast, evidence intimates that licorice root possesses
antioxidant, anti-inflammatory, antiviral, antitumor, and other
protective bioactivities [9–11]. Licorice or its extract have
been used for prevention of hepatitis and allergic reactions
[1], treatment of esophageal inflammation and gastric ulcer [9,
12] and as a depigmentation agent in cosmetic and pharmaceutical products [13].
Licorice root contains a variety of oils, alkaloids, polysaccharides, polyamines, triterpenes, phenolic acids, flavones,
flavans, chalcones, flavonoids, and isoflavonoids [14–16].
The major component of licorice is glycyrrhizin or
glycyrrhizic acid [10, 17] that is hydrolyzed in the intestine
to the active glycyrrhetic acid (GA) by β-glucuronidase [18].
GA in licorice extracts has been associated with mineralocorticoid excess [19] and is a potent inhibitor of 11-βhydroxysteroid dehydrogenase, which can result in increased
cortisol activity [20].
The anti-inflammatory and antioxidant effects of licorice
components and extracts and their potential role in numerous
diseases, including cancer, have been studied extensively.
However, most of the studies are observational in nature and
a direct molecular target has not been unequivocally identified
to explain the potential beneficial effects of licorice. In this
review, we will focus not only on what is known about
glycyrrhizic acid and glycyrrhetic acid (Fig. 1a, b) in cancer
prevention, but also on certain specific components of licorice, which may be less toxic and for which a potential
molecular anticancer target has been identified. The specific
components to be reviewed include the chalcone-type derivative iso-liquiritigenin (ILQ, Fig. 1c), the flavonoid
isoangustone A (IAA, Fig. 1d), and the licochalcones, especially licochalcone A (LicA; Fig. 1e) and E (LicE; Fig. 1f).
Glycyrrhizin and Glycyrrhetic Acid
A number of studies have focused on the bioactivity of
glycyrrhizin (Gc) and glycyrrhetic acid (GA). Gc has been
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used against chronic viral hepatitis [21] and is reportedly
active against a number of other viruses, including latent
Kaposi sarcoma-associated herpes virus [22], severe acute
respiratory distress syndrome (SAR (...truncated)
