Tyrosinase inhibitory effects and inhibition mechanisms of nobiletin and hesperidin from citrus peel crude extracts.
Journal of Enzyme Inhibition and Medicinal Chemistry. 2007 February;22(1):91-8
Zhang et al studied the effect of nobiletin on the enzyme tyrosinase and found that nobiletin inhibited the enzyme (competitive type and non-competitive type of inhibition). Extracts from mandarin peel (Citrus unshiu Marc.) were tested for their inhibitory action on melanogenesis in mouse melanoma cells. The mandarin peel extract showed a significant inhibition while hesperidin showed almost no inhibition. Nobiletin and the extract showed antiproliferation effects but only very low cytotoxity on the melanoma cell.
Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells.
Cancer Science. 2007 April;98(4):471-7
This study investigated the influence of the phytochemicals nobiletin and auraptene on prostate carcinogenesis. The study involved an in-vivo test with using genetically modified rats with prostate adenocarcinoma. Rats were fed with a diet containing nobiletin or auraptene or a basal diet for 15 weeks. The researchers found that the phytochemicals had no influence on prostate weights and serum testosterone levels. Nobiletin caused a significant reduction of specific prostate lobes and decreased high grade lesions in the ventral and lateral lobes. The effects of auraptene were less pronounced. An in-vitro test showed that nobiletin and to a lesser extent auraptene suppressed growth of human prostate cancer cells. The study concluded that these phytochemicals, particularly nobiletin, may be beneficial in the prevention of prostate cancer.
Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats.
Biofactors. 2004;22(1-4):111-4
Azoxymethane is a carcinogen used to induce colon cancer in rodents and to determine the chemopreventative effectiveness of particular foods or chemicals. This rodent model is used to identify chemicals which prevent human colon cancer. This study investigated the effect of nobiletin on rats with azoxymethane-induced colon cancer. The researchers found that the incidence of colonic adenocarcinoma was reduced by the intake of nobiletin group in a dose-dependant manner. They also noticed that nobiletin reduced the proliferation of the colon cancer cells and decreased the prostaglandin E2 content. The study concluded that nobiletin has chemopreventive activity against azoxymethane-induced colon cancer.
Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells.
Bioscience Biotechnology and Biochemistry. 2005 February;69(2):307-14
Some of matrix metalloproteinases is associated with physiological and pathological processes such as the spreading of cancer cells. Kawabata and his colleagues measured the expression of mRNA for matrix metalloproteinases in six human colorectal cancer cell lines and found a one cell line showed considerable expression of matrix metalloproteinases -7. The researchers tried to find chemicals that would reduce this expression. They tested different chemicals and found that nobiletin, quercetin, valeryl salicylate and sulindac sulfone showed a significant inhibition. Nobiletin reduced the binding of activator protein with DNA and attenuated the expression of attenuated pro matrix metalloproteinases -7 protein and its mRNA. The researchers suggested that nobiletin is a promising agent for suppression of cancer cell invasion and spreading.
Inhibition of cell proliferation by nobiletin, a dietary phytochemical, associated with apoptosis and characteristic gene expression, but lack of effect on early rat hepatocarcinogenesis in vivo.
Cancer Science. 2004 Decemer;95(12):936-42
Previous studies have shown that many phytochemicals can inhibit the development of certain types of tumors. Ohnsishi et al studied the effect of several phytochemicals (nobiletin, garcinol, auraptene, beta-cryptoxanthin, hesperidine and 1,1'-acetoxychavicol acetate) on hepatocarcinogenesis in rats. They also measured their effect on cell proliferation, cell cycle kinetics, apoptosis and cell invasion of liver cancer cells. They found no effect of nobiletin on the development of putative liver lesions but nobiletin inhibited the proliferation of the liver cancer cells, caused cell cycle arrest and apoptosis. The study concluded that phytochemicals might have chemopreventive potentials in later stages of liver cancer.
Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: antiproliferative effects, induction of apoptosis and cell cycle deregulation.
Alimentary Pharmacology & Therapeutics. 2004 Jul;20 Suppl 1:95-101
Kubota et al tested the antitumour effects of nobiletin on several cultured stomach cancer cell lines. They found that the citrus flavonoid acted on the cancer cell by direct cytotoxicity, induction of apoptosis and modulation of cell cycle. The also tested the influence of nobiletin on the activity of the drug cisplatin, which is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas, lymphomas and germ cell tumours. The found that pre-treatment of nobiletin had a synergistic effect on the activity cisplatin. The study concluded that nobiletin holds promise as drug to treat gastric cancer, but that more research on this subject is required.
Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of tissue inhibitor of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and -9 in human fibrosarcoma HT-1080 cells.
Cancer Research. 2002 February 15;62(4):1025-9
Sato and colleagues studied the inhibitory effect of nobiletin on tumour invasion of human fibrosarcoma cells. The tumour invasion activity was measured on Matrigel (trade name for a gelatinous protein mixture secreted by mouse tumour cells) model. The migration of tumour cells into this matrix is an indication of tumor cell metastasis. They found that nobiletin inhibited the invasion of the Matrigel. This inhibition was also observed when the tumour cells were treated with tissue inhibitors of matrix metalloproteinases. They treated tumour cells with the tumour promoter TPA and found that nobiletin reduced the production of matrix metalloproteinases and suppressed the binding activity of activator protein-1. The study concluded that nobiletin inhibits tumor cell invasive activity by suppressing the expression of matrix metalloproteinases, by increasing production of matrix metallopeptidase inhibitor 1 and by inhibition of activator protein-1 binding activity.
Dietary administration of citrus nobiletin inhibits azoxymethane-induced colonic aberrant crypt foci in rats.
Life Science. 2001 July 13;69(8):901-13
Kohno et al studied the protective effects of nobiletin on colon cancer induced in rats by the carcinogen azoxymethane with the aberrant crypt foci method. This method is often used to study modulators of carcinogenesis. It provides a simple and economical tool for preliminary screening of potential chemopreventive agents. They found that the dietary administration of nobiletin at a dosage of 0.01% resulted in a 50% reduction of the number of aberrant crypt foci. They also tested the level of Ki67 protein with the antibody MIB-5 to determine the growth rate of the tumour cells. They found that nobiletin significantly lowered MIB-5-index in the foci and reduced prostaglandin E2 level in the colonic mucosa. The study concluded that might have chemopreventive activities through the suppression of cell proliferation.
Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice.
Cancer Research. 2000 September 15;60(18):5059-66
Murakami A et al investigated the effect of the citrus flavonoid nobiletin on the inhibition of production of nitric oxide and superoxide. The production of nitric oxide is linked to epithelial carcinogenesis. First, the researchers carried out an in-vitro test with cultured rat macrophage cells, which were treated with lipopolysaccharide and interferon-gamma to induce the production of the free radical nitric oxide and superoxide. They found that nobiletin inhibited the production of both free radicals. In another test they treated human promyelocytes (leukaemia cells) with the tumour promoter phorbol 12-myristate-13-acetate. Finally they conducted an in-vivo test on mouse skin treated topically with the same tumour promoter.
Nobiletin significantly inhibited skin inflammation by decreasing the inflammatory parameters such as cyclooxygenase-2, inducible NO synthase proteins and prostaglandin E2. Nobiletin also significantly inhibited chemically induced skin tumour formation. The study concluded that nobiletin holds a potential as a chemopreventive drug in inflammation-associated tumorigenesis.
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