Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer.

Yu-An Chen,Yen-Ju Lo,Cheng-Hsun Chiu,Jer-Tsong Hsieh,Chiu-Lien Hung,Yi-Ru Lai,Yu-Hsin Lin,Yu-Fang Chang,Chun-Jung Lin,U-Ging Lo,Ho Lin,Chih-Ho Lai,Hui-Yu Wu

doi:10.3390/biomedicines9020151

Abstract

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by Campylobacter jejuni, is a tripartite genotoxin composed of CdtA, CdtB, and CdtC subunits. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against radioresistant PCa.

Highlights

Prostate cancer (PCa) is a threatening malignancy that has demonstrated an escalating trend in both incidence and mortality rate worldwide in recent years [1]
Similar to the previous results, the foci were observable in all treatment conditions except for the mock control, and hyaluronic acid (HA)-CdtB-NPs/ionizing radiation (IR) cotreatment solely demonstrated maximum foci formation. These results reveal that HA-CdtB-NPs were the most effective and could synergistically enhance IR-induced double-strand breaks (DSBs) in radioresistant
Our results showed that HA-CdtB-NPs exert potent cytotoxic effects in radioresistant PCa cells, further investigations are required to validate their medical application

Summary

Introduction

Prostate cancer (PCa) is a threatening malignancy that has demonstrated an escalating trend in both incidence and mortality rate worldwide in recent years [1]. Patients may develop several non-specific symptoms such as urinary retention, urinary hesitancy, nocturia, Biomedicines 2021, 9, 151. Because of the high heterogeneity of PCa, the relationship between certain symptoms and cancer development is rather weak and undefined [3]. Treatment strategies for PCa include surgery, chemotherapy, hormone therapy, and radiation therapy [4]. Radiation therapy is considered as an effective remedy for localized cancers, which improves prognosis when combined with other appropriate treatment modalities [5,6]. The development of radioresistance often leads to tumor metastasis or relapse [7]. To overcome this problem, a radiation sensitizer is likely to be the solution

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