Extracorporeal Shock Wave Enhances the Cisplatin Efficacy by Improving Tissue Infiltration and Cellular Uptake in an Upper Urinary Tract Cancer Animal and Human-Derived Organoid Model

SIMPLE SUMMARY: Chemotherapy is the standard treatment for advanced upper urinary tract urothelial carcinoma (UTUC), and shock wave treatment is a common strategy for upper urinary tract stones. We explored the mechanism of the combination therapy of low-energy shock waves (LESWs) and cisplatin for UTUC in vitro, in vivo, and in patient-derived organoid (PDO) models. Histopathological examination showed more deteriorated cell arrangement and oedema in the combination treatment group than in the cisplatin only group. Immunohistochemical analysis revealed reduced expression of proliferation markers, increased expression of apoptosis markers, and increased cisplatin infiltration in the combination treatment group. Western blotting revealed decreased cisplatin efflux and membranous protein levels after shock wave application. Moreover, LESW improved the cytotoxicity of cisplatin in the preclinical PDO model of UTUC. Our findings showed that LESW enhanced the antitumour efficacy of cisplatin in UTUC. Hence, combination therapy could have promising applications for locally advanced UTUC in clinical settings. ABSTRACT: Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare cancer with a poor prognosis if diagnosed at an advanced stage. Although cisplatin-based chemotherapy is a common treatment strategy, it has a limited response rate. Shock wave lithotripsy is a common treatment for upper urinary tract stones. Low-energy shock waves (LESWs) temporarily increase tissue permeability and enhance drug penetration to the targeted tissue. However, no study has investigated the efficacy of the combination of shock wave lithotripsy and chemotherapy in UTUC. Hence, in this study, we aimed to identify the potential application of the combination of LESW and chemotherapy in UTUC. We evaluated the synergistic effects of LESW and cisplatin in vitro, in vivo, and in patient-derived organoid (PDO) models. Compared with cisplatin alone, the combination treatment caused more significant tumour suppression in vitro and in animal models, without increased toxicity. Histological examination showed that compared with animals treated with cisplatin alone, those who received the combination treatment showed more deteriorated cell arrangement and cell oedema. Moreover, LESW improved the cytotoxicity of cisplatin in the preclinical PDO model of UTUC. Thus, LESW combined with cisplatin is a potential new antitumour strategy for improving the treatment response in locally advanced UTUC.