Fabiano Abigail R, Newman Malachy W, Dombroski Jenna A, Rowland Schyler J, Knoblauch Samantha V, Kusunose Jiro, Gibson-Corley Katherine N, Kaufman Benjamin G, Ren Liqin, Caskey Charles F, King Michael R
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37235, USA.
Department of Bioengineering, Rice University, Houston, TX, 77005, USA.
Adv Sci (Weinh). 2025 Apr;12(15):e2412995. doi: 10.1002/advs.202412995. Epub 2025 Feb 20.
Non-surgical and safe prostate cancer (PCa) therapies are in demand. Soluble tumor necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL), a cancer-specific drug, shows preclinical efficacy but has a short circulation half-life. This research has shown that physiological fluid shear stress activates mechanosensitive ion channels (MSCs), such as Piezo1, enhancing TRAIL-mediated apoptosis in cancer cells. Herein, noninvasive, focal ultrasound (FUS) is implemented to augment the pro-apoptotic effects of TRAIL. Using thermally safe FUS parameters, it is observed that TRAIL sensitivity increases with higher FUS pressure in PCa cells, mediated by Piezo1. This is confirmed by examining the effects of calcium chelation, MSC inhibitors, and PIEZO knockdown. In vivo, a multi-dose study with 10 min FUS exposure shows that 0 and 4-h intervals between TRAIL and FUS significantly reduce tumor burden, with an increase in apoptosis evident by enhanced cleaved-caspase 3 expression. This mechanotherapy offers a clinically translatable approach by utilizing widely available FUS technology, applicable to treat additional cancer types.
非手术且安全的前列腺癌（PCa）治疗方法备受需求。可溶性肿瘤坏死因子（TNF-α）相关凋亡诱导配体（TRAIL），一种癌症特异性药物，显示出临床前疗效，但循环半衰期较短。本研究表明，生理流体剪切应力可激活机械敏感离子通道（MSC），如Piezo1，增强TRAIL介导的癌细胞凋亡。在此，采用非侵入性聚焦超声（FUS）来增强TRAIL的促凋亡作用。使用热安全的FUS参数，观察到在PCa细胞中，TRAIL敏感性随FUS压力升高而增加，这由Piezo1介导。通过检测钙螯合、MSC抑制剂和PIEZO基因敲低的影响得到了证实。在体内，一项10分钟FUS暴露的多剂量研究表明，TRAIL与FUS之间0和4小时的间隔显著减轻肿瘤负担，通过增强的裂解型半胱天冬酶3表达可明显看出凋亡增加。这种机械疗法通过利用广泛可用的FUS技术提供了一种可临床转化的方法，适用于治疗其他癌症类型。
