硫化氢合成酶抑制剂金丝桃素的体内外抗结肠癌作用研究

To investigate the effect of hypcricin on the activity of hydrogen sulfide producing enzyme and explore the antitumor effects of hypcricin as a cystathionines-synthase (CBS) inhibitor in vitro and in vivo, the inhibitory effect of hypcricin and aminooxyacetic acid (AOAA) on CBS activity was determined by the methylene blue method. Further, HT29 human colon cancer cells and a HT-29 colon cancer xenograft mouse model were used to study the antitumor effect of hypcricin in vitro and in vivo. The results indicated that hypcricin, a photosensitizer in the diagnosis and photodynamie therapy of cancer isolated from medicinal herb Hypcricum perforatum, was identified as a potent and selective inhibitor of CBS with an IC₅₀value of 7. 9 ± 1.42 μmol/L. Hypcricin greatly suppressed the proliferation of HT29 human colon cancer cells with an IC₅₀value of 22. 2 ± 2. 25 μmol/L, and CBS protein could be one of the targets of hypcricin in mammalian cells, as evidenced by CBS knockdown analyses. Surprisingly, AOAA, a commonly used CBS inhibitor, displayed very weak inhibition of HT29 cancer cells with an IC₅₀value of 152. 5 ± 35. 68 μmol/L. This could perhaps be attributed to limited cell membrane permeability of AOAA. Additionally, hypcricin at a dose of 5-30 mg/kg · d significantly inhibited the growth of xenograft tumors compared to the control group. After subcutaneous administration of 30 mg/kg · d for two weeks, the weight of the tumors decreased by 68% compared with the control group. Collectively, these results show that hypcricin as a selective inhibitor of CBS has significant anti-colon cancer activity.