The role of cellular reactive oxygen species in cancer chemotherapy

Abstract

Most chemotherapeutics elevate intracellular levels of reactive oxygen species (ROS), and many can alter redox-homeostasis of cancer cells. It is widely accepted that the anticancer effect of these chemotherapeutics is due to the induction of oxidative stress and ROS-mediated cell injury in cancer. However, various new therapeutic approaches targeting intracellular ROS levels have yielded mixed results. Since it is impossible to quantitatively detect dynamic ROS levels in tumors during and after chemotherapy in clinical settings, it is of increasing interest to apply mathematical modeling techniques to predict ROS levels for understanding complex tumor biology during chemotherapy. This review outlines the current understanding of the role of ROS in cancer cells during carcinogenesis and during chemotherapy, provides a critical analysis of the methods used for quantitative ROS detection and discusses the application of mathematical modeling in predicting treatment responses. Finally, we provide insights on and perspectives for future development of effective therapeutic ROS-inducing anticancer agents or antioxidants for cancer treatment.

Keywords: Cancer; Chemotherapy; Mathematical modeling; ROS detection; Reactive oxygen species (ROS); Redox.

Fig. 1

Many factors contribute to increasing ROS levels in cancer, which in turn lead to a number of biological consequences. Overall, current theories suggest the culmination of increased ROS during cancer development confers a survival advantage, which is increased further during chemotherapy. Chemotherapy pushes ROS levels over a critical threshold proposed to induce biological processes leading to cell death, mostly via apoptosis

Fig. 2

Different chemotherapeutics have distinct mechanisms of action, the diagram represents the cellular mechanisms by which the main classes of chemotherapeutics exhibit their effects. Some chemotherapies, in blue text, impacting ROS production in the cell while others, in orange text, regulate ROS by inhibiting their detoxification by cellular antioxidants. Altered balance of cancer ROS production and removal by chemotherapeutic modulation dictates the final level of ROS and the ultimate outcome of ROS effect

Fig. 3

ROS detection has been performed using a variety of different methods. Indirect analysis of ROS is performed by the analysis of the oxidation products of ROS. More direct methods of ROS analysis include the visualisation of small molecules that convert to an alternative spectrum of fluorescence after ROS mediated oxidation. Protein based probes function with a similar theory, the ROS mediated oxidation of residues in the fluorescent protein alters the emission of the protein enabling localisation of ROS oxidation

Fig. 4

Schematic representation of the mathematical modeling of cancer at an intracellular, cellular and organ scale. Because tumors are heterogeneous entities in a changing microenvironment, development of new chemotherapeutics and understanding the sophisticated cancer redox biology are needed to address the importance of diversity in cancer cell populations and microenvironmental characteristics. Integrating information from multiple levels of biological complexity and multiscale models can potentially be more powerful than focusing solely on the well-developed molecular network level. In this framework, a system of ordinary differential equations could be developed to describe the dynamics of N species, [ROS]1(t), [ROS]2(t), [ROS]3(t) …[ROS]N(t), where the dynamics are governed by the production and decay terms for each ROS species, Pi(t) and Di(t), for i = 1,2,3…N, and t is time. In addition, each ROS species varies both temporally and spatially, such as at the organ-scale, it would be more appropriate to work with a system of partial differential equations. For this situation the mathematical model would predict the spatiotemporal distribution of N species, [ROS]1(x, t), [ROS]2(x,t), [ROS]3(x,t) …[ROS]N(x,t), where t is time and x is spatial position. In this case the spatial transport of each ROS species is governed by the flux J(x,t), which could be used to specify diffusive transport or some kind of directed transport if appropriate