Potentiation of etoposide and vincristine by two synthetic 1,4-dihydropyridine derivatives in multidrug-resistant and atypical multidrug-resistant human cancer cells.

Newly synthesized 1,4-dihydropyridine derivatives had been screened to determine whether they could overcome vincristine (VCR)-resistance in VCR-resistant (P388/VCR) leukemia-bearing mice, and six compounds had strong reversing ability among the screened compounds. We further determined whether NK-250 and NK-252 among the six compounds could potentiate cytocidal activities of etoposide (VP16) as well as VCR against both multidrug-resistant (MDR) cell line (VJ-300) and atypical MDR cell line (KB/VM-4). Both VJ-300 and KB/VM-4 were derived from the same parental human cancer KB cell line: VJ-300 cells showed enhanced expression of a MDR-specific glycoprotein of molecular weight of 170,000 Da (gp170) while KB/VM-4 cells were selected as teniposide (VM26)-resistant cell line with no expression of gp170. NK-250 and NK-252 potentiated the cytotoxic action of VCR about 2- to 10-fold against KB and KB/VM-4 cells, and they almost completely reversed VCR-resistance in VJ-300 cells. By contrast, NK-250 and NK-252 potentiated the cytotoxic action of VP16 about 2-fold against KB cells while they reversed 5- to 10-fold VP16-resistance in both VJ-300 and KB/VM-4 cells. The reversal effect by NK-250 and NK-252 of VCR-resistance in VJ-300 cells appeared to be due to enhanced cellular accumulation of radioactive VCR through interaction to 170-kDa P-glycoprotein. The potentiation effects by these dihydropyridines of VCR and VP16 on KB or KB/VM-4 cells also appeared to be due to enhanced accumulation of radioactive VP16 or VCR, but the effects might be mediated through other mechanisms, plausibly enhanced cellular uptake of the drugs.