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.