From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors.
An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracyclines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.
Kurtoglu
Metin
M
Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Lampidis
Theodore J
TJ
D018943:Anthracyclines / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002412:Cations / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D003847:Deoxyglucose / Q000627:therapeutic use*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012016:Reference Values; D020112:Rhodamine 123 / Q000737:chemistry / Q000627:therapeutic use
D018943:Anthracyclines; D000970:Antineoplastic Agents; D002412:Cations; D020112:Rhodamine 123; D003847:Deoxyglucose