Chapter 27
Inhibitory Effects of Curcumin on Carcinogenesis in Mouse Epidermis 1
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Mou-Tuan Huang , Fredika M . Robertson , Thomas Lysz , Thomas Ferraro , Zhi Yuan Wang , Constantine A. Georgiadis , Jeffrey D. Laskin , and Allan H. Conney 1
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Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855 Department of Surgery, Ohio State University, Columbus, OH 43210 Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Newark, NJ 07103 Department of Environmental and Community Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854
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Curcumin (diferuloylmethane) inhibits tumor initiation by benzo[a]pyrene and tumor promotion by 12-O-tetradecanoylphorbol13-acetate (TPA) in female CD-1 mice. Topical application of curcumin also inhibits benzo[a]pyrene-mediated D N A adduct formation in the epidermis. Co-application of curcumin with T P A inhibits TPA-induced skin inflammation (mouse ear edema), increased epidermal ornithine decarboxylase activity, increased epidermal D N A synthesis, increased epidermal thickness, increased number of epidermal cell layers and leukocyte infiltration. Curcumin also inhibits arachidonic acid-induced edema of mouse ears in vivo and epidermal cyclooxygenase and lipoxygenase activities in vitro. Curcumin and demethoxycurcumin are equipotent as inhibitors of TPA-induced ear inflammation, and bisdemethoxycurcumin and tetrahydrocurcumin are less active. The structurally related dietary compounds chlorogenic acid, caffeic acid and ferulic acid are weak antioxidants, weak inhibitors of TPA-induced increases in epidermal ornithine decarboxylase activity, weak inhibitors of TPA-induced mouse ear inflammation, weak inhibitors of cyclooxygenase and lipoxygenase activity, and weak inhibitors of TPA-induced tumor promotion in mouse skin. Carcinogenesis is a multistage process that can be divided into initiation, promotion and progression. Initiation occurs relatively rapidly (within a few hours to one or two days), while promotion requires long periods of time (up to a year or longer in some rodent models (1). It is estimated that the promotion stage may require up to 30 years or even longer in some people. Although efforts in cancer chemotherapy have intensified over the years, many cancers still remain very difficult to cure and cancer prevention could become an increasingly useful strategy in our fight against cancer. Human epidemiology and animal studies have indicated that cancerriskmay be modified by changes in dietary habits or dietary components (1-4). Humans ingest large numbers of naturally occurring antimutagens and anticarcinogens in food 0097-6156/92/0507-0338$06.00/0 © 1992 American Chemical Society
In Phenolic Compounds in Food and Their Effects on Health II; Huang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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27. HUANG ET AL.
Inhibitory Effects of Curcumin on Carcinogenesis
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(7, 4-6), and these antimutagens and anticarcinogens may inhibit one or more stages of carcinogenesis and delay or prevent the formation of cancer. Recent studies have indicated that compounds with antioxidant and/or anti-inflammatory properties can inhibit tumor initiation and tumor promotion in mouse skin (7-74). Epidemiological studies indicate that dietary factors play an important role in the development of human cancer (2, 75), and attempts to identify naturally occurring dietary anti carcinogens may lead to new strategies for cancer prevention. Curcumin (Figure 1) is the major pigment in turmeric (the ground rhizome of Curcuma longa Linn) which is widely used as a spice and coloring agent in curry, mustard and other foods. Curcumin has been reported to possess antioxidant and anti inflammatory activity (76-79). This paper describes the inhibitory effect of curcumin and some structurally related compounds on chemical carcinogenesis in mouse skin. The effects of curcumin on certain biochemical and morphological markers of carcinogenesis are also described. Effect of C u r c u m i n on Benzo[a]pyrene-Mediated D N A A d d u c t Formation and Benzo[a]pyrene-Induced Tumor Initiation Inhibitory Effect of Curcumin on the Formation of Benzo[a]pyreneMediated D N A Adducts in Mouse Epidermis. Fifteen hours after the application of 20 nmol 3H-benzo[a]pyrene (BP) to the backs of CD-I mice, there was an average of 0.74 pmol of covalently bound adducts per mg of epidermal D N A . Topical application of 3 or 10 μπιοί curcumin 5 minutes before the application of 3H-BP inhibited the formation of BP metabolite DNA-bound adducts by 30 or 61%, respectively (Figure 2). Inhibitory Effect of Curcumin on the Initiation of Skin Tumors by B P . Female C D - I mice (30 per group) that were initiated with 20 nmol of B P once weekly for 10 weeks and then promoted with 15 nmol TPA twice weekly for 21 weeks developed an average of 7.1 skin tumors per mouse. Topical application of 3 or 10 μπιοί curcumin 5 minutes before each application of BP inhibited the number of skin tumors per mouse by 58 or 62%, respectively, after 21 weeks of TPA promotion (Figure 3). Similar results were obtained using a single, high dose of BP. Mice that were initiated with 200 nmol BP and then promoted with 15 nmol TPA twice weekly for 21 weeks developed an average of 6.9 skin tumors per mouse; 77% of the mice had tumors. Topical application of 10 μπιοί curcumin to the skin at 120, 60 and 5 minutes before the application of 200 nmol BP decreased the average number of skin tumors per mouse by 58%, and the percent of mice with tumors was decreased by 23%. In another experiment studying curcumin's effect on BP-induced skin tumori genesis, the topical application of 10 μπιοί curcumin to the backs of mice once daily for 4 days prior to a single application of 200 nmol BP (24 hours after the last dose of curcumin) neither induced nor inhibited the number of skin tumors per mouse or the number of mice with tumors. These observations suggest that curcumin does not induce enzymes that metabolically activate or detoxify BP.
In Phenolic Compounds in Food and Their Effects on Health II; Huang, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.
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PHENOLIC COMPOUNDS IN FOOD AND THEIR EFFECTS ON HEALTH II
Curcumin
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Caffeic acid
