Department of Medicine, Lanzhou University Second Hospital, Gansu Province, China.
Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G929-37. doi: 10.1152/ajpgi.00159.2011. Epub 2011 Aug 11.
DNA mismatch repair is required for correcting any mismatches that are created during replication and recombination, and a defective mismatch repair system contributes to DNA damage-induced growth arrest. The colorectal cancer cell line HCT116 is known to have a mutation in the hMLH1 mismatch repair gene resulting in microsatellite instability and defective mismatch repair. Honokiol is a biphenolic compound that has been used in traditional Chinese medicine for treating various ailments including cancer. This study was designed to test the hypothesis that honokiol enhances the radiosensitivity of cancer cells with mismatch repair defect (HCT116) compared with those that are mismatch repair proficient (HCT116-CH3). We first determined that the combination of honokiol and γ-irradiation treatment resulted in dose-dependent inhibition of proliferation and colony formation in both cell lines. However, the effects were more pronounced in HCT116 cells. Similarly, the combination induced higher levels of apoptosis (caspase 3 activation, Bax to Bcl2 ratio) in the HCT116 cells compared with HCT116-CH3 cells. Cell cycle analyses revealed higher levels of dead cells in HCT116 cells. The combination treatment reduced expression of cyclin A1 and D1 and increased phosphorylated p53 in both cell lines, although there were significantly lower amounts of phosphorylated p53 in the HCT116-CH3 cells, suggesting that high levels of hMLH1 reduce radiosensitivity. These data demonstrate that honokiol is highly effective in radiosensitizing colorectal cancer cells, especially those with a mismatch repair defect.
DNA 错配修复是纠正复制和重组过程中产生的任何错配所必需的，而有缺陷的错配修复系统会导致 DNA 损伤诱导的生长停滞。众所周知，结肠直肠癌细胞系 HCT116 存在 hMLH1 错配修复基因的突变，导致微卫星不稳定和错配修复缺陷。和厚朴酚是一种双酚化合物，已在传统中药中用于治疗各种疾病，包括癌症。本研究旨在检验以下假设：与错配修复功能正常的细胞（HCT116-CH3）相比，和厚朴酚增强具有错配修复缺陷的癌细胞（HCT116）的放射敏感性。我们首先确定，和厚朴酚与γ射线照射联合治疗导致两种细胞系的增殖和集落形成均呈剂量依赖性抑制。然而，在 HCT116 细胞中效果更为明显。同样，与 HCT116-CH3 细胞相比，该联合诱导了更高水平的细胞凋亡（caspase 3 激活，Bax 与 Bcl2 比值）。细胞周期分析显示 HCT116 细胞中死亡细胞水平更高。联合治疗降低了两种细胞系中细胞周期蛋白 A1 和 D1 的表达，并增加了磷酸化 p53 的水平，尽管 HCT116-CH3 细胞中的磷酸化 p53 明显减少，这表明高水平的 hMLH1 降低了放射敏感性。这些数据表明，和厚朴酚在放射增敏结直肠癌细胞，特别是错配修复缺陷的细胞方面非常有效。
