Abstract
BackgroundRecently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers.Methodology/Principal FindingsA high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation.Conclusions/SignificanceThrough our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer. The mechanism of action includes mitochondrial localization causing decreased oxygen consumption, increased superoxide production and attenuated growth factor signaling.
Highlights
Phosphonium salts have broad utility, with applications in chemistry, biology and pharmacology
Conclusions/Significance: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that show remarkable activity in a panel of cancer cell lines as well as in a mouse model of human breast cancer
Studies of phosphonium salts as contrast agents for diagnostic imaging [13,14] have elucidated two key points concerning the selectivity of this class of compounds: 1) these agents are capable of preferentially accumulating within tumor cells, 2) that phosphonium cation itself does not impart cytotoxicity
Summary
Phosphonium salts have broad utility, with applications in chemistry, biology and pharmacology. The distribution of charge across the large lipophilic surface of the phosphonium ion significantly lowers this energy requirement facilitating passage across lipid membranes.[3] phosphonium salts accumulate in energized mitochondria due to their highly negative membrane potential. Based on this observation, the triphenylphosphonium ion has been used as a targeting moiety for delivery of agents such as spin traps, fluorescent dyes, and antioxidants to isolated mitochondria, as well as the mitochondria of intact cells and whole organisms. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers
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