Effects of β-boswellic acids on 12-O-tetradecanoylphorbol-13 acetate-induced inflammation, arachidonic acid metabolism and expression of antioxidant enzyme genes in mouse ears

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An extract of gum resin exudate from the stem of the plant Boswellia serrata has been used as an herbal medicine for centuries in India for the treatment of inflammation, arthritic pain, and other inflammatory related diseases. Recent studies have confirmed the potent anti-inflammatory properties of this extract and have shown that its derivatives induce differentiation and apoptosis of many different cancer cell types. However, few studies have investigated the efficacy of this extract in animal models of carcinogenesis. In the current study, anti-inflammatory properties of the four major active constituents of Boswellin extract, β-Boswellic acid (BA), 3-O-acetyl-β-boswellic acid (ABA), 11-keto-β-boswellic acid (KBA), and 3-O-acetyl-11-keto-basowellic acid AKBA, were tested for efficacy against the potent tumor promoting agent 12-O-tetradecanoyl-phorbol 13-acetate (TPA). A single topical application of TPA (1.5 nmol) on the ears of CD-1 mice rapidly induced a linear increase in ear edema to a maximum within 4-6 hours. Topical application of TPA (0.8 nmol) once a day for 4 days induced persistent inflammation in ears and inflammation persisted linearly for 4-5 days with up-regulation of cytokine IL-1β and IL-6 protein levels in ear tissues. Topical application of individual BA, ABA, KBA and AKBA (10 μmol) 30 min before TPA treatment inhibited TPA-induced edema of mouse ears with the following efficacy: KBA>AKBA>ABA>BA. Topical application of AKBA (0.5 µmol) 10 min prior to each TPA treatment once a day for 4 days inhibited TPA-induced persistent inflammation and up-regulation of pro-inflammatory cytokine IL-1β and IL-6 protein levels. RT-PCR analysis showed that AKBA reduced expression of inflammatory cytokine mRNA. TPA-induced expression of IL-6 and IL-10 was blocked by addition of AKBA, as were inflammatory genes including cyclooxygenase-2 and ornithine decarboylase. Expression of pro-survival and proliferative genes was enhanced by AKBA treatment following TPA exposure; bcl-2, bad, c-myc, and catalase were all stimulated. AKBA enhanced TPA-induced formation of PGE₂ levels and inhibited TPA-induced LTB₄ levels in ear tissue. By blocking the lipoxygenase metabolism pathway and up-regulating the expression of antioxidant enzyme genes, AKBA may possess anti-inflammatory activities. (Supported by CA93798 and CA100994).