Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models

作者：Bowen Jiang, Wenjing Zhang, Ying Wang, Liping Tan, Yongli Bao, Zhenbo Song, Chunlei Yu, Shuyue Wang, Lei Liu, Yuxin Li · 发表于：Biomedicine & Pharmacotherapy · 年份：2019 · DOI：10.1016/j.biopha.2019.109615 · 被引用次数：56 · 研究领域：Cell death mechanisms and regulation、S100 Proteins and Annexins、Psoriasis: Treatment and Pathogenesis

Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantl...