Multidrug resistance phenotypes in human tumours are associated with the overexpression of the 170 kDa
P-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene, and also with that of the non-
P-glycoprotein-mediated multidrug resistance gene, MRP, which encodes a 190 kDa membrane
ATP-
binding protein. We have previously reported that overexpression of MRP appears to be responsible for spontaneous multidrug resistance in some human
glioma cell lines (Abe et al., Int. J.
Cancer, 58, 860-864, 1994). In this study, we investigated whether chemosensitising agents of
P-glycoprotein-mediated multidrug resistance such as
verapamil, a biscoclaurine
alkaloid (
cepharanthine), and a
dihydropyridine analogue (
NIK250) could also reverse multidrug resistance in human
glioma cells. The
glioma cell lines were the two MRP-expressing cell lines, T98G and IN500, an MDR1-expressing cell line, CCF-STTG1, and the
MRP1 MDR1-non-expressing cell line, IN157.
Verapamil and
NIK250 almost completely reversed drug resistance to
vincristine,
etoposide and
doxorubicin in T98G cells, while they also reversed drug resistance to
vincristine and
etoposide, but only partially to
doxorubicin in IN500 cells.
Cepharanthine as well as
verapamil and
NIK250 reversed
vincristine resistance in CCF-STTG1 cells, but
cepharanthine only partially reversed drug resistance in T98G and IN500 cells. The cellular accumulation of [3H]
etoposide increased about 2- and 3-fold compared with control in T98G cells in the presence of
verapamil and
NIK250 respectively. Furthermore, the release of
doxorubicin from the nuclei of T98G cells was blocked by
NIK250. However,
NIK250 and
verapamil caused no apparent increase in
vincristine accumulation in T98G cells.
NIK250 or
verapamil might exert inhibitory effects upon MRP function, resulting in a reversal of MRP-mediated spontaneous multidrug resistance in cultured human
glioma cells.