The quest to quantify selective and synergistic effects of plasma for cancer treatment: Insights from mathematical modeling

TL;DR

This paper develops a mathematical model to quantify the selective and synergistic anti-cancer effects of plasma-treated liquids, highlighting the role of hydrogen peroxide and nitrite in cell susceptibility and response.

Contribution

It introduces a novel mathematical framework to analyze plasma-induced cancer cell responses, focusing on quantifying selectivity and synergy based on cell features.

Findings

Maximal intracellular hydrogen peroxide concentration correlates with cell susceptibility.

The model identifies regimes of selective versus non-selective, and synergistic versus non-synergistic effects.

Proposes new quantitative measures for plasma therapy effectiveness based on cell properties.

Abstract

Cold atmospheric plasma (CAP) and plasma-treated liquids (PTLs) have recently become a promising option for cancer treatment, but the underlying mechanisms of the anti-cancer effect are still to a large extent unknown. Although hydrogen peroxide has been recognized as the major anti-cancer agent of PTL and may enable selectivity in a certain concentration regime, the co-existence of nitrite can create a synergistic effect. We develop a mathematical model to describe the key species and features of the cellular response towards PTL. From the numerical solutions, we define a number of dependent variables, which represent feasible measures to quantify cell susceptibility in terms of the hydrogen peroxide membrane diffusion rate constant and the intracellular catalase concentration. For each of these dependent variables, we investigate the regimes of selective versus non-selective, and of synergistic versus non-synergistic effect to evaluate their potential role as a measure of cell susceptibility. Our results suggest that the maximal intracellular hydrogen peroxide concentration, which in the selective regime is almost four times greater for the most susceptible cells compared to the most resistant cells, could be used to quantify the cell susceptibility towards exogenous hydrogen peroxide. We believe our theoretical approach brings novelty to the field of plasma oncology, and more broadly, to the field of redox biology, by proposing new ways to quantify the selective and synergistic anti-cancer effect of PTL in terms of inherent cell features.