Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Pharmacology. 2018;102(1-2):105-113. doi: 10.1159/000489998. Epub 2018 Jun 28.
Bardoxolone methyl (CDDO-me) is a synthetic triterpenoid that has been shown to suppress various cancers and inflammation. It has been implicated for the suppression of signal transducer and activator of transcription 3 (STAT3)-mediated signaling, which plays crucial roles in the development and progression of hepatocellular carcinoma (HCC). Previously, we showed that hepatitis B virus (HBV) large surface protein (LHB) variant W4P promotes carcinogenesis and tumor progression through STAT3 activation. Thus, we examined the anti-cancer activity of CDDO-me against HCC using W4P-LHB-expressing NIH3T3 cells and HepG2 and Huh7 HCC cell lines. CDDO-me exerted cytotoxic activity against W4P-LHB-expressing NIH3T3 cells, HepG2 cells, and Huh7 cells, and induced apoptotic cell death in a dose-dependent manner, demonstrating its anti-cancer activity against HCC. Sublethal concentrations of CDDO-me suppressed STAT3 activation by W4P-LHB ectopic expression and interleukin-6 treatment in W4P-LHB-NIH3T3 and Huh7 cells respectively. The suppression of STAT3 activation by CDDO-me in W4P-LHB-NIH3T3 cells was further confirmed by decreased cyclin D1 protein levels and increased p21 and p53 mRNA synthesis. In addition, CDDO-me treatment resulted in decreased cell migration and colony formation in in vitro assays using W4P-LHB-NIH3T3, HepG2, or Huh7 cell lines, supporting its anti-cancer activity through STAT3 inhibition. Furthermore, -CDDO-me administration significantly suppressed tumor growth induced by W4P-LHB-expressing NIH3T3 cells in nude mice, confirming its anti-cancer activity. Collectively, our findings demonstrated that CDDO-me is capable of suppressing STAT3 activation in HCC cells and cells transformed by the natural variant of HBV protein. The results suggest that CDDO-me can be a potential therapeutic agent against HCC, especially tumors related to HBV mutations.
Bardoxolone 甲基（CDDO-me）是一种合成三萜类化合物，已被证明可抑制多种癌症和炎症。它被认为可以抑制信号转导和转录激活因子 3（STAT3）介导的信号转导，该信号转导在肝细胞癌（HCC）的发展和进展中起着关键作用。先前，我们表明乙型肝炎病毒（HBV）大表面蛋白（LHB）变体 W4P 通过激活 STAT3 促进癌变和肿瘤进展。因此，我们使用表达 W4P-LHB 的 NIH3T3 细胞以及 HepG2 和 Huh7 HCC 细胞系检查了 CDDO-me 对 HCC 的抗癌活性。CDDO-me 对表达 W4P-LHB 的 NIH3T3 细胞、HepG2 细胞和 Huh7 细胞具有细胞毒性作用，并呈剂量依赖性诱导细胞凋亡，表明其对 HCC 具有抗癌活性。亚致死浓度的 CDDO-me 抑制了 W4P-LHB 异位表达和白细胞介素 6 处理在 W4P-LHB-NIH3T3 和 Huh7 细胞中分别对 STAT3 的激活。CDDO-me 在 W4P-LHB-NIH3T3 细胞中对 STAT3 激活的抑制作用通过降低 cyclin D1 蛋白水平和增加 p21 和 p53 mRNA 合成得到进一步证实。此外，CDDO-me 处理导致在用 W4P-LHB-NIH3T3、HepG2 或 Huh7 细胞系进行的体外测定中细胞迁移和集落形成减少，支持其通过抑制 STAT3 发挥抗癌活性。此外，CDDO-me 给药显著抑制了裸鼠中由表达 W4P-LHB 的 NIH3T3 细胞诱导的肿瘤生长，证实了其抗癌活性。总之，我们的研究结果表明，CDDO-me 能够抑制 HCC 细胞和由 HBV 蛋白天然变体转化的细胞中的 STAT3 激活。结果表明，CDDO-me 可以成为针对 HCC 的潜在治疗剂，特别是与 HBV 突变相关的肿瘤。
