Chemopreventive activity

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Konoshima, T. et al.. Cancer chemopreventive activity of an iridoid glycoside, 8-acetylharpagide, fvom Ajuga decumbens. Cancer I tt., 157, 87, 2000. 

In addition to their possible prooxidant activity (see above) polyphenols and flavonoids may influence cancer cells via their antioxidant properties. Recently, Jang et al. [219] studied cancer chemopreventive activity of resveratrol, a natural polyphenolic compound derived from grapes (Chapter 29). These authors showed that resveratrol inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. Flavonoids silymarin and silibinin also exhibited antitumor-promoting effects at the stage I tumor promotion in mouse skin [220] and manifested antiproliferative effects in rat prostate cancer cells [221]. 

Fahmy H, Khalifa S, KonoshtmaT, Zjawiony JK, Potent cancer chemopreventive activity, Marine Drugs 2 1—7, 2002. 

Several studies have shown the ability of DNMT inhibitors to prevent cancer using different pathways [101-104]. Genistein demonstrated cancer chemopreventive activities in animal models [105]. It has been studied in different cancer cell lines and inhibition of cancer cell growth has been shown [106]. But several mechanisms, such as antihormonal effects, are discussed to explain this activity and the exact contribution of DNMT inhibition to in-vivo activity in cancer chemoprevention remains to be determined. 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

Kawamori T, Rao CV, Seibert K, et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 1998 58 409-412. 

S. M. Fischer, H.-H. Lo, G.B. Gordon, K. Seibert, G. Kelloff, R.A. Lubet, C.J. Conti, Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol. Carcinog. 25 (1999) 231. 

Ito, C. et al., Chemical constituents of Millettia taiwaniana structure elucidation of five new isoflavonoids and their cancer chemopreventive activity. Journal of Natural Products, 67, 1125, 2004. 

Cadalene reduced the incidence of adenomas and inhibited the development of induced lung tumorigenesis in mice [361], while carvacrol inhibited growth of myoblast cells [362]. Menthol exhibited chemopreventive activity against induced rat mammary cancer [363]. 

Lambert JD, Yang CS. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat Res 2003 523-524 201-208. 

Structures of compounds with potential cancer chemopreventive activity. 

Using the technique of activity-guided chromatographic isolation, it is possible to generate many structurally novel bioactive plant secondary metabolites, and examples have been provided in this chapter of plant secondary metabolites with potential anticancer or potential cancer chemopreventive activity, comprised by compounds representative of the chal-cone, flavanone, flavone, furocoumarin, isoflavone, lignan, oligostilbenoid (resveratrol... 

G., Moon, R. C., and Pezzuto, J. M., 1997, Cancer chemopreventive activity of resveratrol, a natural product derived lfom grapes, Science 275 218-220. 

Many of the hop s constituents, including valerianic acid, have a sedative effect, and it is now used to treat insomnia, restlessness, and anxiety. Its bitter principals, humulon and lupulon, are gastrointestinal stimulants used to treat indigestion and loss of appetite. These bitter acids also have antibacterial and antimicrobial properties. The hop is believed to contain chemicals that promote menstruation, and certain flavonoids have shown potential chemopreventive activity against breast and ovarian cancer. 

It is clear that the chemopreventive activity of garlic is related to the organosulfur compounds (OSCS) derived from garlic. Although how garlic achieves chemoprevention is not fully understood, several modes of action have been proposed on the basis of recent studies. 

Monoterpenoids have been isolated from the fragrant oils of many plants and are important in the perfumery and flavor industry. A number of these dietary monoterpenoids have chemopreventive activity [33,34]. 

Synthetic 13-m-retinoic acid not only inhibited the incidence but also reduced the severity of bladder neoplasms induced by the intravesical administration of MNU of female Wister-Lewis rats [113]. In an experimental model with mice treated with TV-butyl-A -(4-hydroxybutyl)-nitrosamine (OH-BBN), retinoic acid (Re5), 13-cw-retinoic acid, and retinol acetate (Re2) show chemopreventive activity. In addition, a quite large number of synthetic -alkyl amide derivatives of Re2 have a greater activity to toxicity ratio than 13-cw-retinoic acid [113]. 

Both cell cultures and animal studies have shown that many of the naturally occurring mono-, sesqui-, di-, sester-, and meroterpenoids as well as retinoids possess potentially chemopreventive activities. Terpenoids are minor but ubiquitous components of our diet, and have the advantage of being non-toxic or relatively non-toxic to humans. More mechanistic-oriented basic research is needed to elucidate the mechanisms of action. Studies of derivatives of these naturally occurring terpenoids are also necessary to elucidate the structure-activity relationship and to guide the development of novel chemopreventive agents. 

Amin, A., Alkaabi, A., Al-Falaasi, S. and Daoud, S.A. (2005) Chemopreventive activities of Trigonella foenum-graecum (Fenugreek) against breast cancer. Cell Biology International 29(8), 687-694. 

Itoigawa, M., Ito, C., Tokuda, H., Enjo, F., Nishino, H. and Furukawa, H. (2004) Cancer chemopreventive activity of phenylpropanoids and phytoquinoids from lllicium plants. Cancer Letters 214(2), 165-1 69. 

Wu et al., 2005). Atrovirisidone B isolated from G. atroviridis showed cytotoxic activity against human breast, prostate and large cells. Cancer chemopreventive activity was exhibited by G. assugu plants (Ito et al., 2003a) and also by G. fusca plants (Ito et al., 2003b). 

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