Deoxypodophyllotoxin suppresses Malignant pleural mesothelioma growth via mitotic dependent necroptosis. Deoxypodophyllotoxin suppresses Malignant pleural mesothelioma growth via mitotic dependent necroptosis

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with a poor prognosis. Patients are typically diagnosed at an advanced stage due to the disease's long incubation period. Limited therapeutic advancements in the last two decades have prompted further investigation into alternative treatments. Previous studies have identified significant dysregulation in the mitotic spindle assembly checkpoint pathway and microtubule network of MPM, underscoring the potential of targeting microtubules in managing MPM. Deoxypodophyllotoxin (DPT) is a novel microtubule-targeting drug that has demonstrated promising therapeutic efficacy in various cancers. While the precise mechanism of DPT's anti-MPM effect remains undisclosed, our research indicates that DPT inhibits MPM growth in a dose-dependent manner both in vitro and in vivo. Moreover, it exhibits a favorable safety profile and shows lower toxicity towards normal cells and mice at therapeutic doses. Mechanistic studies involving three MPM cell lines (MSTO-211H, H2452, and H28) revealed that DPT induces multinucleated and micronucleated cells, disrupts spindle formation, and triggers Mitosis cell cycle arrest and necroptosis in tumor cells. In conclusion, our findings suggest that DPT holds promise as a safe and effective therapeutic option for MPM. Overall design: Extract total RNA from MPM H2452 cells treated with DPT (20nM) or DMSO (control) 48h. We analyzed the differentially expressed genes between the treatment group and the control group using RNA. Both groups were treated in four biological replicates.

恶性胸膜间皮瘤（Malignant pleural mesothelioma, MPM）是一种高度侵袭性肿瘤，预后极差。由于该病潜伏期较长，患者通常在疾病晚期才得以确诊。近二十年来治疗手段进展有限，促使研究者进一步探索替代疗法。既往研究已证实，MPM的有丝分裂纺锤体组装检查点通路与微管网络存在显著失调，这凸显了靶向微管用于MPM治疗的潜力。脱氧鬼臼毒素（Deoxypodophyllotoxin, DPT）是一种新型微管靶向药物，在多种癌症中已展现出颇具前景的治疗效果。尽管DPT抗MPM的确切作用机制尚未阐明，但本研究证实，DPT在体外与体内实验中均以剂量依赖的方式抑制MPM生长。此外，其安全性良好，在治疗剂量下对正常细胞与小鼠的毒性更低。针对三种MPM细胞系（MSTO-211H、H2452及H28）的机制研究显示，DPT可诱导肿瘤细胞形成多核细胞与微核细胞，破坏纺锤体形成，并触发肿瘤细胞的有丝分裂周期阻滞与坏死性凋亡。综上，本研究结果表明DPT有望成为一种安全有效的MPM治疗选择。
实验整体设计：将经脱氧鬼臼毒素（20nM）或二甲基亚砜（DMSO，对照组）处理48小时的MPM H2452细胞提取总RNA。我们利用RNA对处理组与对照组间的差异表达基因进行分析。两组均设置四次生物学重复。