Selective Inhibition of Respiration of Pigmented S91 Mouse Melanomas by Phenyl Lactate, and the Possibly Related Effects on Growth

Summary

The tyrosinase inhibitor, DL-β-phenyl lactic acid (PLA), decreased O₂ consumption in cells of pigmented S91 melanomas, but not in amelanotic cells of the same tumor. This inhibition of respiration, which could be demonstrated in a tyrosine-free medium, was accompanied by a simultaneous increase in aerobic glycolysis. Since the specific PLA-susceptible respiratory segment in melanotic S91 cells might represent tyrosinase activity, it has been suggested that this enzyme plays a vital respiratory role, perhaps involving oxidative phosphorylation. PLA was effective in reducing O₂ consumption only when present from “0” time. When its addition was delayed until the preparations were consuming O₂ for some time, inhibition did not develop except where a short (4 min) period of anaerobiosis was interpolated. Growth studies in vitro correlated well with the manometric results. PLA in levels of 1 to 1.5 mM per liter selectively prevented growth of melanotic S91 explants if present at 0 time in their growth curve. Delayed addition of PLA to cultures that were incubated for more than 2 hours in normal medium was without effects. The selectivity of PLA was not as marked in tissue culture as it was manometrically, since higher concentrations of this agent affected growth of nonmelanotic control tissues as well. Suggestions are given to account for the decreased specificity of PLA in tissue culture. This inhibitor also prevented growth of mclanotic S91 tumors freshly transplanted into young DBA/2 mice while growth of their somatic tissues was not impaired, but it had no effects on established tumors.