The novel anthracycline annamycin is not affected by P-glycoprotein-
related multidrug resistance: comparison with idarubicin and doxorubicin in
HL-60 leukemia cell lines
U Consoli, W Priebe, YH Ling, R Mahadevia, M Griffin, S Zhao, R Perez-Soler and M Andreeff
Department of Hematology, University of Texas M.D. Anderson Cancer Center,
Houston, USA.
A major factor in limiting the efficacy of anthracyclines is overexpression
of the MDR1-encoded p-glycoprotein (p-gp). A new analogue less affected by
p-gp is annamycin (ANN), an anthracycline antibiotic with high affinity for
lipid membranes and significantly more activity than doxorubicin (DOX). We
investigated whether ANN was affected by p-gp-mediated multidrug resistance
(MDR) by comparing the cellular accumulation and retention of ANN,
idarubicin (IDR), and DOX in the p-gp-negative human leukemia cell lines
(HL-60S) and its DOX- selected p-gp-positive subline (HL-60/DOX) with and
without verapamil (VER). As expected, HL-60/DOX cells showed lower DOX
uptake than HL-60S cells; coincubation with VER (10 mmol/L) increased
uptake 2.6-fold restoring it to 100% of uptake in HL-60S cells. IDR uptake
increased 1.5-fold in the presence of VER, but ANN was not affected.
Coincubation with VER increased DOX retention in HL-60/DOX cells 2.8-fold
and IDR retention 1.4-fold; unchanged ANN retention indicated that ANN may
overcome p-gp. In the cytotoxicity assay to correlate intracellular
anthracycline content with antitumor activity, we found ANN to be less
potent than DOX and IDR In sensitive cells, ID 50 being the drug
concentration that inhibits cell growth by 50% but its resistance index
(RI; ID50 resistant cells divided by ID50 sensitive cells) was lower than
that of IDR and DOX (2.6 v 40 and 117.5). Coincubation in the presence of
VER resulted in 4.5-fold and 2-fold RI decreases of DOX and IDR,
respectively, whereas ANN did not change, further confirming ANN's ability
to circumvent p-gp-mediated MDR. Confocal microscopy studies of IDR, ANN,
and DOX showed higher intracellular drug compartmentalization for DOX in
HL-60/DOX cells incubated in the presence of VER. This study provided
evidence that, unlike DOX and IDR, ANN is not affected by p-gp- mediated
MDR.
Volume 88,
Issue 2,
pp. 633-644,
07/15/1996
Copyright © 1996 by The American Society of Hematology
