Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Oxid Med Cell Longev. 2021 Jan 4;2021:7689045. doi: 10.1155/2021/7689045. eCollection 2021.
Hepatocellular carcinoma (HCC) is a leading cause of death, resulting in over 700 thousand deaths annually worldwide. Chemotherapy is the primary therapeutic strategy for patients with late-stage HCC. Heteronemin is a marine natural product isolated from sp. that has been found to protect against carcinogenesis in cholangiocarcinoma, prostate cancer, and acute myeloid leukemia. In this study, heteronemin was found to inhibit the proliferation of the HCC cell lines HA22T and HA59T and induce apoptosis via the caspase pathway. Heteronemin treatment also induced the formation of reactive oxygen species (ROS), which are associated with heteronemin-induced cell death, and to trigger ROS removal by mitochondrial SOD2 rather than cytosolic SOD1. The mitogen-activated protein kinase (MAPK) signaling pathway was associated with ROS-induced cell death, and heteronemin downregulated the expression of ERK, a MAPK that is associated with cell proliferation. Inhibitors of JNK and p38, which are MAPKs associated with apoptosis, restored heteronemin-induced cell death. In addition, heteronemin treatment reduced the expression of GPX4, a protein that inhibits ferroptosis, which is a novel form of nonapoptotic programmed cell death. Ferroptosis inhibitor treatment also restored heteronemin-induced cell death. Thus, with appropriate structural modification, heteronemin can act as a potent therapeutic against HCC.
肝细胞癌 (HCC) 是全球主要的死亡原因之一，每年导致超过 70 万人死亡。化疗是晚期 HCC 患者的主要治疗策略。异海松烷是一种从 sp. 中分离出来的海洋天然产物，已被发现可预防胆管癌、前列腺癌和急性髓性白血病的癌变。在这项研究中，异海松烷被发现可抑制 HCC 细胞系 HA22T 和 HA59T 的增殖，并通过半胱天冬酶途径诱导细胞凋亡。异海松烷处理还诱导活性氧 (ROS) 的形成，ROS 与异海松烷诱导的细胞死亡有关，并通过线粒体 SOD2 而不是细胞质 SOD1 触发 ROS 清除。丝裂原活化蛋白激酶 (MAPK) 信号通路与 ROS 诱导的细胞死亡有关，异海松烷下调与细胞增殖相关的 ERK（一种 MAPK）的表达。与凋亡相关的 JNK 和 p38 的 MAPK 抑制剂恢复了异海松烷诱导的细胞死亡。此外，异海松烷处理降低了抑制铁死亡的蛋白 GPX4 的表达，铁死亡是一种新型的非凋亡程序性细胞死亡。铁死亡抑制剂处理也恢复了异海松烷诱导的细胞死亡。因此，经过适当的结构修饰，异海松烷可以作为治疗 HCC 的有效药物。
