Cold-atmospheric plasma induces tumor cell death in preclinical in vivo and in vitro models of human cholangiocarcinoma

TL;DR

Cold atmospheric plasma (CAP) shows promise as a novel therapy for cholangiocarcinoma by inducing DNA damage, cell cycle arrest, and apoptosis in tumor cells both in vivo and in vitro, with potential to improve treatment outcomes.

Contribution

This study demonstrates the antitumor effects of CAP on cholangiocarcinoma in preclinical models and elucidates the underlying molecular mechanisms involved.

Findings

CAP induces DNA lesions and apoptosis in tumor xenografts

CAP causes dose-dependent decrease in CCA cell survival in vitro

CAP activates DNA damage response pathways leading to cell cycle arrest

Abstract

Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA both in an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. Analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, incubation of CCA cells with CAP-treated culture media (i.e. plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future.