Abstract
Pharmacological concentrations of small molecule natural products, such as ascorbic acid, have exhibited distinct cell killing outcomes between cancer and normal cells whereby cancer cells undergo apoptosis or necrosis while normal cells are not adversely affected. Here, we develop a mathematical model for ascorbic acid that can be utilized as a tool to understand the dynamics of reactive oxygen species (ROS) induced cell death. We determine that not only do endogenous antioxidants such as catalase contribute to ROS-induced cell death, but also cell membrane properties play a critical role in the efficacy of ROS as a cytotoxic mechanism against cancer cells vs. normal cells. Using in vitro assays with breast cancer cells, we have confirmed that cell membrane properties are essential for ROS, in the form of hydrogen peroxide (H2O2), to induce cell death. Interestingly, we did not observe any correlation between intracellular H2O2 and cell survival, suggesting that cell death by H2O2 is triggered by interaction with the cell membrane and not necessarily due to intracellular levels of H2O2. These findings provide a putative mechanistic explanation for the efficacy and selectivity of therapies such as ascorbic acid that rely on ROS-induced cell death for their anti-tumor properties.
Highlights
Antioxidants are key determinants of the cancer cell killing efficacy of natural products such as ascorbic acid
We investigated how reactive oxygen species (ROS) contributes to cell death and used ascorbic acid as the basis for our model
Utilizing kinetics based on known scientific literature of ascorbic acid activity in cancer cells and normal cells, we developed a mathematical model that predicted a mechanism of cell death via induction of H2O2
Summary
To understand the cancer cell killing behavior of ascorbic acid, we start by considering the chemical reactions that govern the cell’s defensive mechanisms against H2O2 Cells employ their detoxifying machinery to protect themselves against H2O2 damage, primarily in the form of two antioxidant systems, catalase and glutathione peroxidase. If the intracellular concentration of H2O2 is Chin2to[2] assuming a standard diffusive membrane transport term, the rate of H2O2 transfer into the cell due to ascorbic acid is given by. For high production rates of H2O2, which is the case when cells are in a high concentration of ascorbic acid, we obtain the following equation (in this equation we separate the effects of external and internal sources of H2O2). NIS Elements Viewer version 3.22 (Nikon, Melville NY) software was used to capture the images to file
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
