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

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.

Use of the Shock Wave Therapy in Basic Research and Clinical Applications—From Bench to Bedsite

“…A decrease in the activity of inflammatory biomarkers seems to be a potential mechanism of action in observed in improvement in symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS) in human [25,26]. These clinical findings have been confirmed in a recently published meta-analysis [27] regarding the therapy of patients with a chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Additionally, similar encouraging clinical outcomes of SWT have been reported regarding the therapy of overactive bladder syndrome (OAB) [28,29].…”

“…Attenuated inflammatory responses, enhanced angiogenesis protein expression, and the elevated protein phosphorylation of ErK1/2, P38, and Akt along with areversion of mitochondria function dysregulation [30] seems to play a crucial role in these processes. Notably, the SWT can also modulate the way of administration and enhanced delivery of Botulinum toxin serotype A (BoNT/A), commonly used in the bladder and urinary tract diseases [27,31].…”

DNA Hypomethylation Is Associated with the Overexpression of INHBA in Upper Tract Urothelial Carcinoma

“…Slides carrying tissue sections cut from formalinfixed, paraffin-embedded tissue microarray blocks were dried for 1 h at 60 • C. These slides were then covered by Bond Universal Covertiles and placed in the Bond-Max instrument. All subsequent steps were performed automatically by the instrument according to the manufacturer's instructions (Leica Microsystems) as documented in a previous report [51]. Primary antibody reaction: INHBA (1:100; cat# sc-166503, Santa Cruz, CA, USA), and the reaction was conducted at RT for 60 min.…”

Mutational pattern off homologous recombination repair (HRR)‐related genes in upper tract urothelial carcinoma

“…2 Renal insufficiency is common in UTUC patients, and thoes patients are ineligible for certain treatments, although cisplatin-based chemotherapy was currently the most effective chemotherapy agent for UC. 4,5 Immune checkpoint inhibitors (ICIs) are extensively applied to the management of UC; however, they have a limited response rate in UTUC patients. 6 Therefore, improving the efficacy of treatment and exploring new therapeutic strategies are clinical challenges.…”

“…UTUC and UC of the bladder (UCB) had similar histologic appearance; however, UTUC shows a more advanced presentation than UCB, and more than 60% of patients have invasive disease at the time of diagnosis 2 . Renal insufficiency is common in UTUC patients, and thoes patients are ineligible for certain treatments, although cisplatin‐based chemotherapy was currently the most effective chemotherapy agent for UC 4,5 . Immune checkpoint inhibitors (ICIs) are extensively applied to the management of UC; however, they have a limited response rate in UTUC patients 6 .…”