Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, South Korea.
Phytomedicine. 2010 Dec 1;17(14):1127-32. doi: 10.1016/j.phymed.2010.03.013.
TPA is a potent regulator of cell growth, including cell proliferation and differentiation. In this study, we determined the effect of silibinin on TPA-induced growth arrest in breast cancer cells. Silibinin increased growth arrest of the G2/M phase in a dose-dependent fashion. Silibinin decreased the basal level of cyclin B1 and cdc2 expression, which is involved in S phase and G2/M transition. In addition, TPA-induced G2/M phase arrest was increased by silibinin. Under the same conditions, TPA-induced down-regulation of cyclin B1 and cdc2 was decreased by silibinin. In contrast, TPA-induced p21 expression was further increased by silibinin. To determine the regulatory mechanism of TPA-induced growth arrest, we pretreated cells with various inhibitors, such as UO126, SB203580, and LY294002. Interestingly, TPA-induced growth arrest was significantly increased by LY294002, but not by UO126 and SB203580. In addition, TPA-induced down-regulation of cyclin B1 was inhibited by LY294002; however, the basal level of p21 was increased by TPA and TPA-induced p21 expression was further increased by LY294002. Finally, adenoviral constitutively active-Akt (Ad-CA-Akt) overexpression regulated the up-regulation of cyclin B1 and the down-regulation of p21. Therefore, we have demonstrated that silibinin has an additive effect on TPA-induced growth arrest through the PI-3-kinase/Akt-dependent pathway.
TPA 是细胞生长的有效调节剂，包括细胞增殖和分化。在这项研究中，我们确定了水飞蓟素对 TPA 诱导的乳腺癌细胞生长抑制的影响。水飞蓟素以剂量依赖的方式增加 G2/M 期的生长停滞。水飞蓟素降低了参与 S 期和 G2/M 转换的 cyclin B1 和 cdc2 的基础表达水平。此外，水飞蓟素增加了 TPA 诱导的 G2/M 期阻滞。在相同条件下，水飞蓟素降低了 TPA 诱导的 cyclin B1 和 cdc2 的下调。相比之下，水飞蓟素进一步增加了 TPA 诱导的 p21 表达。为了确定 TPA 诱导的生长抑制的调节机制，我们用各种抑制剂预处理细胞，如 UO126、SB203580 和 LY294002。有趣的是，LY294002 显著增加了 TPA 诱导的生长抑制，但 UO126 和 SB203580 则没有。此外，LY294002 抑制了 TPA 诱导的 cyclin B1 下调；然而，p21 的基础水平被 TPA 上调，而 TPA 诱导的 p21 表达被 LY294002 进一步上调。最后，腺病毒组成型激活 Akt（Ad-CA-Akt）过表达调节了 cyclin B1 的上调和 p21 的下调。因此，我们已经证明，水飞蓟素有协同作用，通过 PI-3-激酶/Akt 依赖性途径增强 TPA 诱导的生长抑制。
