SELECTIVE CYTOTOXICITY OF TOPOISOMERASE-DIRECTED PROTOBERBERINES AGAINST GLIOBLASTOMA CELLS

Protoberberines are a new class of organic cations that are dual poiso ns of topoisomerases I and II. Certain protoberberines exhibit greater in vitro cytotoxicity against cell lines derived from solid tumors th an from leukemias. Using a group of seventeen different protoberberine analogs, the structural basis for selective cytotoxicity toward sensi tive SF-268 glioblastoma cells as compared with resistant RPMI 8402 ly mphoblast cells was explored. The selective cytotoxicity is associated with the presence of an imminium ion and other structural features of protoberberines, and is not shared by drugs such as camptothecin, dox orubicin, vinblastine, and etoposide, which are either equally or more cytotoxic against RPMI 8402 cells than SF-268 cells. The selective cy totoxicity of protoberberines against SF-268 over RPMI 8402 cells is n ot due to differences in topoisomerase levels or known drug efflux sys tems such as multidrug resistance (MDR1) and multidrug-resistance prot ein (MRP). Comparative in vitro studies of the accumulation of coralyn e, a fluorescent protoberberine, into sensitive and resistant cells de monstrated a correlation between drug accumulation and selective cytot oxicity. Inhibitors of coralyne uptake included several protoberberine related compounds. Of these, palmatine, a minimally cytotoxic protobe rberine, both inhibited coralyne accumulation and reduced cytotoxicity against SF-268 cells, but not against RPMI 8402 cells. Despite the st ructural resemblance of protoberberines to catecholamines, our experim ents using inhibitors and cells expressing biogenic amine uptake syste ms have ruled out the involvement of biogenic amine uptake,, uptake(2) , and vesicular monoamine transport systems. Uptake systems remaining as candidates, supported by preliminary data, include transport via ve sicles derived from specialized membrane invaginations and selected ca rrier-mediated organic amine transport systems. (C) 1998 Elsevier Scie nce Inc.