Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea.
Reproduction. 2020 Dec;160(6):919-929. doi: 10.1530/REP-20-0377.
Placental choriocarcinoma is a malignant trophoblastic tumor associated with placentation. During placentation, complicated molecular networks are mediated by endocrine and paracrine signals. Serotonin neurotransmitters have been identified in the transmembrane region of human placental choriocarcinoma (HPC) cells as tumor promoters; therefore, their antagonists have anti-cancer properties. Although methiothepin, a serotonin receptor antagonist and FDA-approved psychotropic agent, has shown multi-pharmacological functions in various disease models, its anti-tumorigenic activity and mechanisms underlying its action against HPC are unknown. Therefore, we identified the anti-cancer effects of methiothepin in JEG3 and JAR HPC cells. Methiothepin attenuated mitochondrial function and induced endoplasmic reticular stress, reducing oxidative phosphorylation and causing metabolic shifting in HPC cells. Furthermore, methiothepin showed synergistic pharmacological effects with paclitaxel in HPC cells. Our results highlight the robust tumor-suppressive function of methiothepin in HPC. Our findings provide new insights into the repositioning of methiothepin from a psychotropic agent to novel anti-cancer agents, especially against HPC.
胎盘绒毛膜癌是一种与胎盘有关的恶性滋养细胞肿瘤。在胎盘形成过程中，内分泌和旁分泌信号介导复杂的分子网络。已在人胎盘绒毛膜癌细胞（HPC）的跨膜区域鉴定出 5-羟色胺神经递质作为肿瘤促进剂；因此，它们的拮抗剂具有抗癌特性。虽然麦硫因，一种 5-羟色胺受体拮抗剂和 FDA 批准的精神药物，在各种疾病模型中表现出多种药理作用，但它对 HPC 的抗肿瘤活性及其作用机制尚不清楚。因此，我们确定了麦硫因在 JEG3 和 JAR HPC 细胞中的抗癌作用。麦硫因减弱了线粒体功能并诱导内质网应激，降低了氧化磷酸化并导致 HPC 细胞发生代谢重编程。此外，麦硫因在 HPC 细胞中与紫杉醇表现出协同的药理作用。我们的结果强调了麦硫因在 HPC 中的强大肿瘤抑制功能。我们的发现为麦硫因从精神药物重新定位为新型抗癌药物，特别是针对 HPC 提供了新的见解。
