The potent anti-tumor-promoting agent isoliquiritigenin

Abstract

A topical application of a chalcone derivative, 4,2',4'-trihydroxychalcone (isoliquiritigenin) inhibited epidermal ornithine decarboxylase (ODC) induction and ear edema formation, i.e. inflammation, caused by a topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in CD-1 mice. In addition, isoliquiritigenin potently inhibited 7,12-dimethylbenz[alpha]anthracene (DMBA)-initiated and TPA-promoted skin papilloma formation. This inhibitory effect of isoliquiritigenin was not due to any damage inflicted on the initiated cells but due to its anti-tumor-promoting action. Isoliquiritigenin also inhibited epidermal ODC induction and skin tumor promotion caused by 7-bromomethylbenz[alpha]anthracene (BrMBA), a non-TPA type of tumor-promoting agent, in DMBA-initiated mice. Isoliquiritigenin inhibits neither 12-lipoxygenase nor cyclooxygenase in epidermal subcellular fractions. This compound, however, inhibited TPA-stimulated prostaglandin E2 (PGE2) production in intact epidermal cells. ODC induction caused by TPA was inhibited by a topical application of cyclooxygenase inhibitor, indomethacin. Inhibition of ODC induction by indomethacin was counteracted by a topical application of PGE2, while inhibition caused by isoliquiritigenin was not overcome by PGE2. The results suggest that a mechanism other than the inhibition of PGE2 production is involved in the anti-tumor-promoting action of isoliquiritigenin. Isoliquiritigenin failed to inhibit phospholipase A2 activity of platelet sonicates, but inhibited platelet 12-lipoxygenase and 5-lipoxygenase in polymorphonuclear leukocytes. Therefore, it might be possible that isoliquiritigenin exerts its anti-tumor-promoting action through the lipoxygenase inhibition by acting on cells other than the target epidermal cells. Our present results, in combination with our previous data, demonstrate that some chalcone derivatives and flavonoids which show a potent lipoxygenase inhibitory action act on a common step in the skin tumor promotion caused by two different types of tumor-promoting agents, i.e. TPA and BrMBA, and suggest that these compounds show promise as drugs to prevent tumor promotion.

Pharmacokinetics, biodistribution and bioavailability of isoliquiritigenin after intravenous and oral administration

“…Isoliquiritigenin (ISL), a flavonoid with chalcone structure (2,4,4 0 -trihydroxychalcone), which exists in licorice and in vegetables including shallots and bean sprouts (Cao et al, 2004;Ii et al, 2004;Kape et al, 1992), has been shown to exhibit a variety of biological activities, including antioxidant (Chin et al, 2007;Haraguchi et al, 1998), antiinflammatory (Kim et al, 2008), estrogenic properties (Tamir et al, 2001), analgesic (Chan et al, 1998;Morteza et al, 2004), cytoprotective effects (Kim et al, 2004), antiplatelet aggregation (Chisato et al, 2008;Tawata et al, 1992), antipeptic ulcer actions (Kim et al, 2006), chemopreventive agent (Hsu et al, 2005a), antiangiogenic effect (Kobayashi et al, 1995), radical-scavenging activity (Yamamoto et al, 1991) and antitumor activities (Baba et al, 2002;Iwashita et al, 2000;Jung et al, 2006b;Kanazawa et al, 2003;Ma et al, 2001;Maggiolini et al, 2002;Takahashi et al, 2004;Yamazaki et al, 2002). In particular, ISL can suppress proliferation of many types of cancer cells and induce their apoptosis, including HL-60 human promyelocytic cell line (Chowdhury et al, 2005), colon cancer cells (Takahashi et al, 2004), gastric cancer cells (Ma et al, 2001), breast cancer cells (Maggiolini et al, 2002), human prostate cancer (Jung et al, 2006a,b) and human hepatoma cells (Hsu et al, 2005b).…”

Studies on Cancer Chemoprevention by Traditional Folk Medicines XXV. Inhibitory Effect of Isoliquiritigenin on Azoxymethane-Induced Murine Colon Aberrant Crypt Focus Formation and Carcinogenesis.

“…inhibitory effect on aldose reductase, 6) anti-tumor promoting effect on two-stage skin tumor formation, 5) suppressive effect against 5-lipoxygenase, 5) antioxidative and superoxide scavenging activities, 8) etc. Topical application of ILG suppress the 12-O-tetra-decanoylphorbol-13-acetate (TPA) or bromomethylbenz [a]anthracen-induced skin tumor formation, 5) and acute inflammation in mouse ear, 5) however, oral administration of this compound showed weak activity on two-stage lung and skin carcinogenesis in our previous studies (unpublished data). These results indicated that the suppressive effect of ILG might be due to direct action against the organs.…”

“…4) Other biological activities for this compound have also been reported. For example, antitumor promoting activity on two-stage mouse skin carcinogenesis, 5) inhibitory effect on aldose reductase activity, 6) antiplatelet aggregation effect, 7) antioxidative and superoxide scavenging activities, 8) etc. However, all these experiments were in vitro or topical application in vivo, and there is no reported data of the effect by oral administration in vivo.…”

Dietary chalcones with chemopreventive and chemotherapeutic potential

“…This compound inhibited TPA-independent tumor promotion in mice treated with DMBA and suppressed TPA-stimulated production of PGE2 in intact epidermal cells. However, it seems that isoliquiritigenin (2) exerts its antitumor-promoting effect through the lipoxygenase (LOX) inhibition in nonepidermal cells because it failed to inhibit 12-LOX and COX in an epidermal subcellular fraction [177]. Ye et al [182] recently demonstrated that isoliquiritigenin (2) inhibits the CYP19 enzyme (aromatase), which catalyzes rate-limiting step of the conversion of androgens, such as testosterone and androstenedione to estrogens.…”