Drug-induced reactive oxygen species (ROS) rely on cell membrane properties to exert anticancer effects.
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.
Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
Hamid R
HR
Molavian
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Aaron
A
Goldman
Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
Colin J
CJ
Phipps
Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.
Mohammad
M
Kohandel
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5T 2M9, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON, M5S 3E2, Canada.
Bradly G
BG
Wouters
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.|Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.|Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Shiladitya
S
Sengupta
Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, N2L 3G1, Canada.|Center for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, Ontario M5T 3J1, Canada.
Sivabal
S
Sivaloganathan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002470:Cell Survival; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008962:Models, Theoretical; D009336:Necrosis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase; D001205:Ascorbic Acid