Metabolites of 3'-O-acetylhamaudol Isolated from Angelica japonica Roots, and their Antitumor Actions
Objective: We previously reported antitumor effects of 3'-O-acetylhamaudol isolated from Angelica japonica roots. However, 3'-O-acetylhamaudol could not be detected in blood after its oral administration. In this study, we examined the antitumor effects and mechanisms of action of metabolites of 3-O-acetylhamaudol. Methods: Metabolites of 3'-O-acetylhamaudol were isolated from blood plasma by HPLC. The effects of hamaudol on tumor growth and tumorinduced angiogenesis were examined in colon 26-bearing mice. Furthermore, the effects of the metabolites on VEGFinduced VEGFR-2 phosphorylation were investigated in HUVECs.
Key Findings: Metabolites of 3'-O-acetylhamaudol were identified as hamaudol and 8-hydroxymethylhamaudol. Hamaudol (25 and 50 mg/kg) inhibited tumor growth, final tumor weight and metastasis to the abdomen in colon 26-bearing mice. Hamaudol (10 mg/kg) also inhibited tumor-induced angiogenesis in tumor-packed chamber-bearing mice. Blood plasma after the oral administration of 3-O-acetylhamaudol (containing hamaudol and 8-hydorxymethylhamaudol), hamaudol and 8-hydroxymethylhamaudol inhibited VEGF-induced angiogenesis and VEGF-induced VEGFR-2 phosphorylation in HUVECs, and enhanced the production of IL-12 and IFN-γ induced by Con A in splenocytes.
Conclusions: The antitumor effects of 3'-O-acetylhamaudol were due to the anti-angiogenic actions of hamaudol and/or 8-hydroxymethylhamaudol.
Keywords: Angelica japonica, metabolites of 3'-O-acetylhamaudol, anti-angiogenesis, antitumor, hamaudol, 8-hydroxymethylhamaudol, endothelial cells, metastasis, mice, roots
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