Xu Dao Gun, Lv Wang, Dai Chun Yan, Zhu Fan Fan, Xu Gua Hua, Ma Zhong Jun, Chen Zhe
Department of Colorectal Surgery, Wenling Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Wenling, China.
Anat Rec (Hoboken). 2015 Feb;298(2):376-85. doi: 10.1002/ar.23045. Epub 2014 Sep 15.
2-(Pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3-diynyl) thiophene (PYDDT) is a naturally occurring thiophene isolated from the roots of Echinops grijsii, a Chinese herbal medicine used to treat colon cancer, breast cancer, and lung cancer. There are many reports on the clinical use of Echinops grijsii alone or in combination with other herbs to treat malignant tumors. We previously reported that the expression and activity of phase II enzymes including GSTs and NQO1 could be induced through the activation of Keap1-Nrf2 pathway by the treatment of PYDDT. In this study, we reported the anticancer effect and mechanism of PYDDT against human colon cancer SW620 cells. Our results demonstrate that treatment of SW620 cells with PYDDT leads to induction of mitochondrial-mediated apoptosis, which is characterized by the cleavage of PARP, activation of caspase 9 and caspase 3, release of cytochrome c from mitochondria, loss of mitochondrial membrane potential, down-regulation of Bcl-2, and mitochondrial translocation of Bax. The PYDDT treatment caused the production of reactive oxygen species (ROS), and the activation of JNK but not p38 mitogen-activated protein kinases and ERK1/2. Specific JNK inhibitor SP600125 prevented the PYDDT-induced down-regulation of Bcl-2, mitochondrial translocation of Bax, activation of caspase 3, and apoptosis of SW620 cells. Moreover, PYDDT-induced apoptosis as well as activation of JNK was abrogated by the pretreatment with antioxidant N-acetylcysteine. Taken together, these findings suggest that PYDDT induces apoptosis in SW620 cells through a ROS/JNK-mediated mitochondrial pathway.
2-（丙-1-炔基）-5-（5,6-二羟基戊-1,3-二炔基）噻吩（PYDDT）是一种天然存在的噻吩，从蓝刺头的根部分离得到，蓝刺头是一种用于治疗结肠癌、乳腺癌和肺癌的中草药。关于单独使用蓝刺头或与其他草药联合使用治疗恶性肿瘤的临床应用有许多报道。我们之前报道过，通过用PYDDT处理激活Keap1-Nrf2途径，可以诱导包括谷胱甘肽S-转移酶（GSTs）和醌氧化还原酶1（NQO1）在内的II期酶的表达和活性。在本研究中，我们报道了PYDDT对人结肠癌SW620细胞的抗癌作用及其机制。我们的结果表明，用PYDDT处理SW620细胞会导致线粒体介导的凋亡，其特征为聚（ADP-核糖）聚合酶（PARP）的裂解、半胱天冬酶9（caspase 9）和半胱天冬酶3（caspase 3）的激活、细胞色素c从线粒体的释放、线粒体膜电位的丧失、Bcl-2的下调以及Bax的线粒体易位。PYDDT处理导致活性氧（ROS）的产生以及JNK的激活，但不包括p38丝裂原活化蛋白激酶和细胞外信号调节激酶1/2（ERK1/2）的激活。特异性JNK抑制剂SP600125可阻止PYDDT诱导的Bcl-2下调、Bax的线粒体易位、caspase 3的激活以及SW620细胞的凋亡。此外，用抗氧化剂N-乙酰半胱氨酸预处理可消除PYDDT诱导的凋亡以及JNK的激活。综上所述，这些发现表明PYDDT通过ROS/JNK介导的线粒体途径诱导SW620细胞凋亡。
