Anticancer Properties and Mechanisms of Singly-Protonated Dehydronorcantharidin Silver Coordination Polymer in a Bladder Cancer Model.

Changkuo Zhou,Weiqiang Jing,Ganyu Wang,Hu Guo,Xuejie Tan

doi:10.3389/fphar.2021.618668

Abstract

Bladder cancer is the most common malignant urinary system tumor. Chemotherapy is frequently used as a treatment regimen for patients with bladder cancer, however, new and effective drugs for bladder cancer need to be developed. The present study examined the effects and mechanisms of Ag-SP-DNC, a silver and singly-protonated dehydronorcantharidin complex, on bladder cancer in vitro and in vivo. It was identified that Ag-SP-DNC suppressed cell proliferation and induced apoptosis in bladder cancer cells in vitro, a suppression associated with G0/G1 phase arrest and elevated intracellular reactive oxygen species (ROS) levels. Furthermore, Ag-SP-DNC enhanced the cleaved caspase-3 levels, disrupted the mitochondrial transmembrane potential balance, and induced intracellular calcium overload. The Ag-SP-DNC-induced bladder cancer cell apoptosis was significantly decreased following treatment with a broad caspase inhibitor, zVAD-fmk. In addition, treatment of MB49 tumor-bearing mice with Ag-SP-DNC significantly inhibited tumor growth and decreased the anti-apoptosis and cell cycle promotion protein levels in the tumor. The results of the present study suggested that Ag-SP-DNC elicits a strong anticancer effect against bladder cancer, and can therefore be used as a promising treatment for bladder cancer.

Highlights

Cancer is a major public health problem worldwide, with bladder cancer being the 4th most commonly diagnosed cancer in men in the United States (Antoni et al, 2017; Siegel et al, 2020)
These data suggested that Ag-SP-DNC inhibited bladder cancer cell proliferation and reduced the Ki67 expression levels
Results showed that caspase inhibition by Z-VAD-FMK leads to the protection of bladder cancer cells from Ag-SP-DNC-induced cell apoptosis (Figures 7E–H). These results demonstrated that the anti-proliferative effect of AgSP-DNC in bladder cancer cells is a consequence of apoptosis dependent on caspase-3 activation

Summary

Introduction

Cancer is a major public health problem worldwide, with bladder cancer being the 4th most commonly diagnosed cancer in men in the United States (Antoni et al, 2017; Siegel et al, 2020). 70% of bladder cancers are non-muscle-invasive bladder cancers upon initial diagnosis, which usually have a relatively favorable prognosis but are associated with considerable morbidity and a high treatment cost (Chang et al, 2016; Robertson et al, 2018). A major aim in the treatment of bladder cancer is the prevention of tumor recurrence and progression. Treatment regimens for bladder cancer and their efficacy vary depending on disease stage, grade and associated risk factors (Alifrangis et al, 2019). The standard treatment for patients with an intermediate-to-high risk of recurrence consists of intravesical administration of agents including Bacillus Calmette-Guérin and mitomycin C (Packiam et al, 2017).

Objectives

Methods

Results

Conclusion