Phosphonium salts exhibiting selective anti-carcinoma activity in vitro.
Tetraphenylphosphonium cation (TPP) and other phosphonium cations selectively inhibited the growth in vitro of human pancreatic carcinoma-derived cells (PaCa-2) and Ehrlich Lettre Ascites cells (ELA) when compared with untransformed monkey kidney epithelial cells (CV-1). In contrast, neither cisplatin nor cytosine arabinoside showed significant selectivity using these lines. Evidence is presented to support the conclusion that the carcinoma-selective antiproliferative activity of phosphonium salts is due to selective accumulation caused by the abnormally high membrane potentials in carcinoma cells. Inhibition of TPP uptake into PaCa-2 and ELA cells by potassium and (for PaCa-2) valinomycin demonstrates that higher membrane potentials account for the carcinoma-selective uptake and cytostatic selectivity of the cation. For TPP chloride and 16 other phosphonium chlorides with a variety of structures, selective inhibition of PaCa-2 growth relative to CV-1 was optimal for the eight falling in a narrow range of octanol/water partition coefficients (between 0.013 and 0.24). A similar optimal selectivity range was observed for ELA cells relative to CV-1. The relationship between partition coefficients and cytostatic selectivity suggests that the rates of diffusion across cytoplasmic and mitochondrial membranes are key factors in the structure/anticarcinoma selectivity relationship for delocalized phosphonium salts in vitro. The relationship could prove useful for the design of other carcinoma-selective delocalized cations.
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Department of Molecular Biology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
Calogeropoulou
T
T
Jaworski
J S
JS
Dagnino
R
R
McCarthy
M R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008970:Molecular Weight; D009861:Onium Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009861:Onium Compounds; D009943:Organophosphorus Compounds; C013289:tetraphenylphosphonium