Kee Ji-Ye, Han Yo-Han, Park Jinbong, Kim Dae-Seung, Mun Jeong-Geon, Ahn Kwang Seok, Kim Hyun-Jung, Um Jae-Young, Hong Seung-Heon
1 Wonkwang University, Iksan, Republic of Korea.
2 Kyung Hee University, Seoul, Republic of Korea.
Integr Cancer Ther. 2017 Dec;16(4):585-596. doi: 10.1177/1534735416681638. Epub 2016 Dec 5.
β-Lapachone is a quinone-containing compound found in red lapacho ( Tabebuia impetiginosa, syn. T avellanedae) trees. Lapacho has been used in traditional medicine by several South and Central American indigenous people to treat various types of cancer. The purpose of this study was to investigate the antimetastatic properties of β-lapachone and the underlying mechanisms using colon cancer cells.
This research used metastatic murine colon cancer cell lines, colon 26 (CT26) and colon 38 (MC38). A WST assay, annexin V assay, cell cycle analysis, wound healing assay, invasion assay, western blot analysis, and real-time reverse transcription-polymerase chain reaction were performed to examine the effects of β-lapachone on metastatic phenotypes and molecular mechanisms. The effect of β-lapachone on lung metastasis was assessed in a mouse experimental metastasis model.
We found that the inhibition of proliferation of the colon cancer cell lines by β-lapachone was due to the induction of apoptosis and cell cycle arrest. β-Lapachone induced the apoptosis of CT26 cells through caspase-3, -8, and -9 activation; poly(ADP-ribose) polymerase cleavage; and downregulation of the Bcl-2 family in a dose- and time-dependent manner. In addition, a low concentration of β-lapachone decreased the cell migration and invasion by decreasing the expression of matrix metalloproteinases-2 and -9, and increased the expression of tissue inhibitors of metalloproteinases-1 and -2. Moreover, β-lapachone treatment regulated the expression of epithelial-mesenchymal transition markers such as E- and N-cadherin, vimentin, β-catenin, and Snail in CT26 cells. In the mouse experimental metastasis model, β-lapachone significantly inhibited the lung metastasis of CT26 cells.
Our results demonstrated the inhibitory effect of β-lapachone on colorectal lung metastasis. This compound may be useful for developing therapeutic agents to treat metastatic cancer.
β-拉帕醌是一种含醌化合物，存在于红拉帕乔树（Tabebuia impetiginosa，同物异名T avellanedae）中。拉帕乔已被南美洲和中美洲的一些原住民用于传统医学中治疗各种类型的癌症。本研究的目的是使用结肠癌细胞研究β-拉帕醌的抗转移特性及其潜在机制。
本研究使用转移性小鼠结肠癌细胞系，结肠26（CT26）和结肠38（MC38）。进行了WST检测、膜联蛋白V检测、细胞周期分析、伤口愈合检测、侵袭检测、蛋白质印迹分析和实时逆转录-聚合酶链反应，以研究β-拉帕醌对转移表型和分子机制的影响。在小鼠实验性转移模型中评估了β-拉帕醌对肺转移的影响。
我们发现β-拉帕醌对结肠癌细胞系增殖的抑制作用是由于诱导细胞凋亡和细胞周期停滞。β-拉帕醌通过激活半胱天冬酶-3、-8和-9；切割聚（ADP-核糖）聚合酶；以及以剂量和时间依赖性方式下调Bcl-2家族，诱导CT26细胞凋亡。此外，低浓度的β-拉帕醌通过降低基质金属蛋白酶-2和-9的表达减少细胞迁移和侵袭，并增加金属蛋白酶组织抑制剂-1和-2的表达。此外，β-拉帕醌处理调节了CT26细胞中上皮-间质转化标志物如E-钙黏蛋白、N-钙黏蛋白、波形蛋白、β-连环蛋白和Snail的表达。在小鼠实验性转移模型中，β-拉帕醌显著抑制了CT26细胞的肺转移。
我们的结果证明了β-拉帕醌对结直肠癌肺转移的抑制作用。这种化合物可能有助于开发治疗转移性癌症的治疗药物。
