ACCUMULATION OF SIMPLE ORGANIC CATIONS CORRELATES WITH DIFFERENTIAL CYTOTOXICITY IN MULTIDRUG-RESISTANT AND MULTIDRUG-SENSITIVE HUMAN AND RODENT CELLS

Citation
Tj. Lampidis et al., ACCUMULATION OF SIMPLE ORGANIC CATIONS CORRELATES WITH DIFFERENTIAL CYTOTOXICITY IN MULTIDRUG-RESISTANT AND MULTIDRUG-SENSITIVE HUMAN AND RODENT CELLS, Leukemia, 11(7), 1997, pp. 1156-1159
Citations number
21
Categorie Soggetti
Hematology,Oncology
Journal title
ISSN journal
08876924
Volume
11
Issue
7
Year of publication
1997
Pages
1156 - 1159
Database
ISI
SICI code
0887-6924(1997)11:7<1156:AOSOCC>2.0.ZU;2-L
Abstract
Structure/functional studies previously reported showed that in a seri es of simple organic cations in which the charge is delocalized, an ar omatic ring and a minimal degree of lipophilicity (log P > -1) were re quired for recognition by murine cells which express P-glycoprotein (p -gp)-mediated multidrug resistance (MDR). In the present report we fin d that H-3-octylpyridinium, the simple aromatic cation which has been shown to be preferentially toxic to MDR- as compared to MDR+ cells, ac cumulates 4.7-fold greater in the MDR- cell line, In contrast, we find that H-3-guanidinium which displays no selective toxicity between MDR + and MDR- cells, shows no significant uptake differences between thes e two cell types. We also present data which demonstrate that other or ganic cations which contain aromatic rings, a minimal degree of lipoph ilicity (log P>-1) and carry a delocalized (Rho 123) or shielded (trip henylmethyl phosphonium) positive charge, also accumulate to a greater degree in MDR- vs MDR+ cells. Additionally, we find that human cells which express p-gp MDR, have similar requirements for recognition of t hese simple compounds. In fact, the sensitivity profiles of these comp ounds closely correlate between murine and human cell lines. It was al so found that none of the series of simple organic compounds tested sh owed modulatory activity in MDR+ cells, as assayed by monitoring reten tion of Rho 123. Thus, the requirements for MDR recognition vs those f or MDR modulation are clearly distinguished with these simple structur ed compounds. In comparison, the calcium channel antagonist, verapamil , and a calcium channel agonist, Bay K 8644, both showed modulatory ac tivity by increasing Rho 123 retention in MDR+ cells, further supporti ng the interpretation that verapamil's modulation of MDR is unrelated to its action on calcium flux. Overall, the data presented here add fu rther information for defining the structural requirements of compound s for their recognition by, or modulation of, human cells expressing p -gp-mediated MDR.