Chapter 33
Anticarcinogenesis of Licorice and Its Major Triterpenoid Constituents
Downloaded by UNIV OF CALIFORNIA SAN FRANCISCO on December 13, 2014 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0547.ch033
Zhi Yuan Wang Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855-0789
Licorice (Glycyrrhiza glabra L.) is a traditional herb widely used as a food sweetening and flavoring agent. Oral administration of a water extract of licorice (1% in drinking water) to female A/J mice throughout the experimental period afforded significant protection against benzo[a]pyrene (BP)- or N-nitrosodiethylamine (NDEA)induced lung and forestomach tumorigenesis. The main water soluble constituent of licorice is glycyrrhizin (GL), a pentacyclic triterpene. Feeding 0.05% GL in the drinking water to female Sencar mice gave substantial protection against 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumor initiation. Glycyrrhetinic acid (GA) is an aglycone of GL which exists in 18α-GA and 18βGA stereoisomeric forms. Topical treatment of female Sencar mice with both isomers significantly inhibited DMBA-induced skin tumor initiation as well as 12-O-tetradecanoylphorbol-13-acetate (TPA)induced skin tumor promotion. Possible mechanisms were studied. Our results indicate that triterpenoids (e.g., glycyrrhetinic acids) may be useful cancer chemopreventive agents.
Licorice (Glycyrrhiza glabra L.) has been used as an antidote, demulcent and elixir folk medicine in China for thousands of years. In addition, licorice is also widely used in the food industry as a food sweetening and flavoring agent in candy, chewing gum, chocolate, cigarettes, liquors and beer. The main water soluble constituent of licorice is glycyrrhizin (GL), a saponin of pentacyclic triterpene derivative of β-amyrin type. GL has been shown to possess several important pharmacological activities, such as an antiinflammatory effect. GL has been shown to be partly hydrolyzed by glucuronidase to its aglycone, glycyrrhetinic acid (GA), which exists in 18α-GA and 18β-GA stereoisomeric forms. Our prior studies have shown that oral administration of GL inhibited DMBA-induced skin tumorigenesis in Senear mice (1) and topical application of 18α-GA and 18β-GA inhibited skin tumor initiation and promotion in Senear mice (2). We also demonstrated that oral administration of water extracts of licorice inhibited BP and DMBA-induced lung and forestomach tumorigenesis in A/J mice (3). In this review the anticarcinogenic effects of licorice and its major triterpenoid constituents are summarized. 0097-6156/94/0547-0329$06.00/0 © 1994 American Chemical Society
In Food Phytochemicals for Cancer Prevention II; Ho, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
330
FOOD PHYTOCHEMICALS II: TEAS, SPICES, AND HERBS
Downloaded by UNIV OF CALIFORNIA SAN FRANCISCO on December 13, 2014 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/bk-1994-0547.ch033
Anticarcinogenesis of Licorice Female A/J mice (6-8 weeks old, Jackson Laboratories, Bar Harbor, ME) were fed Purina Chow 5001 diet (Ralston-Purina Co., St. Louis, MO). Ten g licorice root (cut into small pieces) was extracted with 500 ml boiling water for 30 min and then filtered. The licorice root was extracted a second time with another 500 boiling water and filtered. The combined extract was referred as 1% water extract of licorice. The protective effects of licorice against BP-induced lung and forestomach tumorigenesis in female A/J mice are summarized in Table I. The mice were treated with BP (100 mg/kg administered p.o. at 2-week intervals for 8 weeks) then sacrificed 33 weeks after the last BP treatment. Lung tumors were found in all the animals and the average number of tumors per mouse was 8.7 ± 0.7. Oral feeding of 1.0% water extract of licorice as the sole source of drinking water during the BP treatment (initiation) period caused a 20% reduction in lung tumor incidence, and a 60% reduction in lung tumor multiplicity. Treatment of A/J mice with BP also induced forestomach tumors in 96% of the mice and an average of 2.1 ± 0.3 tumors per mouse. Oral administration of 1.0% water extract of licorice caused a 33% reduction in lung tumor incidence, and 24% reduction in lung tumor multiplicity. The inhibitory effect of licorice on NDEA-induced lung and forestomach tumorigenesis is also shown in Table I. The mice were treated with N D E A (20 mg/kg administered p.o. once weekly for 8 weeks) then sacrificed 33 weeks after the last N D E A treatment. Lung tumors were found in 92% of the animals and the average number of tumors per mouse was 2.9 ± 0.5. Oral administration of 1.0% water extract of licorice as the sole source of drinking water during the N D E A treatment period caused a 26% reduction in lung tumor incidence, and a 55% reduction in lung tumor multiplicity. Treatment of A/J mice with N D E A induced forestomach tumors in 80% of the mice and an average of 2.5 ± 0.7 tumors per mouse. Oral administration of 1.0% licorice water extract caused a 45% reduction in lung tumor incidence, and a 68% reduction in lung tumor multiplicity. In both experiments all forestomach tumors were papillomas and all lung tumors were adenomas. Anticarcinogenesis of Glycyrrhizin Female Senear mice (6-8 weeks old, obtained from the National Cancer Institute Frederick Cancer Research Facility) were used in a DMBA/TPA-induced two-stage skin tumorigenesis protocol. A single topical application of 40 nmol D M B A followed after one week by application of 4 nmol TPA twice weekly for 16 weeks resulted in a 100% skin tumor incidence and 51 ± 4 skin tumors per mouse. Oral administration of 0.05% G L (as ammonium salt, purchased from Sigma Chemical) as the sole source of drinking water for 50 days prior to D M B A application (group GL-1) or 112 days post-DMBA application (group GL-2) both afforded protection against skin tumor initiation (Table II). The latent period prior to the onset of tumor development was prolonged in GL-fed animals compared with the control groups. The time at which 100% of the animals exhibited tumors in the control, GL-1 and GL-2 groups was after 8, 14 and 16 weeks of TPA application, respectively. After
In Food Phytochemicals for Cancer Prevention II; Ho, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
In Food Phytochemicals for Cancer Prevention II; Ho, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
10.7 9.5
9.2 10.3
BP-induced tumorigenesis BP alone 25 + 1 % licorice water extract 25
NDEA-induced tumorigenesis N D E A alone 25 + 1% licorice water extract 25
c
b
a
a
92 68** (26%)
100 80 (20%)
0
13
c
2.9 ± 0.5 1.3 ± 0 . 3 * (55%)
8.7 ± 0.7 3.4 ± 0 . 8 *
0
Tumor incidence Tumors per mouse
Lung tumors
44** (45%)
80
96 64**
0
15
c
2.5 ± 0.7 0.8 ± 0.3* (68%)
2.1 ± 0 . 3 1.6 ± 0 . 5 (24%)
0
Tumor incidence Tumors per mouse
Forestomach tumors
2
Gain from 8 to 42 weeks of age. Percent of mice with tumors. The number in parentheses is the percent protection. **Significantly different from positive control ( χ test, p
