Effects of the glucosphingolipid synthesis inhibitor, PDMP, on lysosomes in cultured cells.

Abstract

The glucosphingolipid synthesis inhibitor, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) has a wide range of effects on cell physiology and morphology. Here, we studied the effects of high concentrations of PDMP on cells in culture and found that fluorescent analogs of PDMP targeted to the lysosomes of Chinese hamster ovary (CHO) cells. Overnight incubation of the cells in the presence of drug induced enlargement (“vacuolization”) of the lysosomes. PDMP was toxic at high concentrations (> 30 microM); this finding was used to select CHO cells that exhibited increased resistance to PDMP (PDMPR cells). The PDMPR cells were approximately 2-fold more resistant to PDMP than the parental cells (CHO-P). PDMPR cells were resistant to a number of other drugs that are also lipophilic and possess a titratable amino group. The multidrug resistance exhibited by the PDMPR cells was distinct from that observed in cells (MDR cells) that overproduce the plasma membrane drug pump, P-glycoprotein. In addition, MDR cells were extremely sensitive to PDMP.