PubMed · 9648297
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W G Weinberg. 1998. Fighting germs.. https://pubmed.ncbi.nlm.nih.gov/9648297/
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Traditional chemotherapies, aimed at DNA replication in rapidly dividing cells, have achieved only limited success in the treatment of carcinomas due largely to their lack of specificity for cells of tumorigenic origin. It is important, therefore, to investigate treatment strategies aimed at novel cellular targets that are sufficiently different between normal cells and cancer cells so as to provide a basis for selective tumor cell killing. Delocalized lipophilic cations (DLCs) are concentrated by cells and into mitochondria in response to negative inside transmembrane potentials. The higher plasma and/or mitochondrial membrane potentials of carcinoma cells compared to normal epithelial cells account for the selective accumulation of DLCs in carcinoma mitochondria. Since most DLCs are toxic to mitochondria at high concentrations, their selective accumulation in carcinoma mitochondria and consequent mitochondrial toxicity provide a basis for selective carcinoma cell killing. Several of these compounds have already displayed some degree of efficacy as chemotherapeutic agents in vitro and in vivo. The effectiveness of DLCs can also be enhanced by their use in photochemotherapy or combination drug therapy. Discovery of the biochemical differences that account for the higher membrane potentials in carcinoma cells is expected to lead to the design of new DLCs targeted specifically to those differences, resulting in even greater selectivity and efficacy for tumor cell killing.
Triclosan is a broad-spectrum hydrophobic antibacterial agent used in dermatological preparations and oral hygiene products. To gain further insight into the mode of action of Triclosan we examined its effects on membranes by performing leakage titrations of different oral bacteria and studying its interaction with model membranes through the use of different biophysical techniques. There was negligible efflux of intracellular material from Streptococcus sobrinus at the minimal inhibitory concentration of Triclosan; whatever leakage did occur commenced only at much higher concentrations. In contrast, no leakage was observed at even the minimal bactericidal concentration for Porphyromonas gingivalis. Triclosan decreased the onset temperature of the gel to liquid-crystalline phase transition of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-3-[phospho-rac-glycerol] membranes and was immiscible with these lipids in the fluid phase at concentrations greater than 5 mol%. Steady-state fluorescence anisotropy measurements of different phospholipid/Triclosan samples using 3-(p-6-phenyl-1,3,5-hexatrienyl)-phenylpropionic acid were consistent with the calorimetric data. Incorporation of increasing amounts of Triclosan into 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE) vesicles induced the nonlamellar H(II) hexagonal phase at low temperatures and new immiscible phases at temperatures below the main transition of DEPE. Taking these results together suggests that the antibacterial effects of Triclosan are mediated at least in part through its membranotropic effects, resulting in destabilized structures which compromise the functional integrity of cell membranes without inducing cell lysis.
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