Selective Anti-Cancer Effects of Plasma-Activated Medium and Its High Efficacy with Cisplatin on Hepatocellular Carcinoma with Cancer Stem Cell Characteristics.

Yan Li,Tianyu Tang,Kiwon Song,Hae June Lee

doi:10.3390/ijms22083956

Abstract

Hepatocellular carcinoma (HCC) is a major histological subtype of primary liver cancer. Ample evidence suggests that the pathological properties of HCC originate from hepatic cancer stem cells (CSCs), which are responsible for carcinogenesis, recurrence, and drug resistance. Cold atmospheric-pressure plasma (CAP) and plasma-activated medium (PAM) induce apoptosis in cancer cells and represent novel and powerful anti-cancer agents. This study aimed to determine the anti-cancer effect of CAP and PAM in HCC cell lines with CSC characteristics. We showed that the air-based CAP and PAM selectively induced cell death in Hep3B and Huh7 cells with CSC characteristics, but not in the normal liver cell line, MIHA. We observed both caspase-dependent and -independent cell death in the PAM-treated HCC cell lines. Moreover, we determined whether combinatorial PAM therapy with various anti-cancer agents have an additive effect on cell death in Huh7. We found that PAM highly increased the efficacy of the chemotherapeutic agent, cisplatin, while enhanced the anti-cancer effect of doxorubicin and the targeted-therapy drugs, trametinib and sorafenib to a lesser extent. These findings support the application of CAP and PAM as anti-cancer agents to induce selective cell death in cancers containing CSCs, suggesting that the combinatorial use of PAM and some specific anti-cancer agents is complemented mechanistically.

Highlights

Hepatocellular carcinoma (HCC), which accounts for 70–90% of primary liver cancers [1], is one of the five most common cancers worldwide and has a poor prognosis.High heterogeneity and recurrence rates are the major characteristics of HCC [2]
We showed that the Cold atmospheric-pressure plasma (CAP)-exposed plasma-activated medium (PAM) as well as the CAP generated from a dielectriccold barrier discharge (DBD)-type device using air as a source of gas was very effective in selectively inducing cell death in HCC cell lines, in Hep3B cells, which harbor a subpopulation of liver
We have demonstrated that air-based CAP effectively induced cell death in HCC cell lines containing cancer stem cells (CSCs) subpopulations, Hep3B and Huh7, especially in Hep3B

Summary

Introduction

Hepatocellular carcinoma (HCC), which accounts for 70–90% of primary liver cancers [1], is one of the five most common cancers worldwide and has a poor prognosis. High heterogeneity and recurrence rates are the major characteristics of HCC [2]. Recent studies have suggested that cancer stem cells (CSCs), a subpopulation of cancer cells, are responsible for HCC initiation, recurrence, and hierarchical organization of heterogeneous cancer cells [3]. CSCs possess stem cell-like properties and can undergo self-renewal and differentiation. It has been reported that specific subsets of CSCs confer high rates of recurrence and therapeutic resistance [4,5]. Liver CSCs can be identified using several well-established cell-surface markers such as epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH), and CD133 [4,6,7,8].

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