The ability of verapamil to restore intracellular accumulation of anthracyclines in multidrug resistant cells depends on the kinetics of their uptake

被引:35
作者
Mankhetkorn, S [1 ]
Garnier-Suillerot, A [1 ]
机构
[1] Univ Paris Nord, CNRS, UA 2056, Lab Physicochim Biomol & Cellulaire, F-93017 Bobigny, France
关键词
multidrug resistance; P-glycoprotein; verapamil; daunorubicin; anthracycline; kinetics; cyclosporin;
D O I
10.1016/S0014-2999(97)01548-3
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance is a decrease of steady state drug levels as compared to those in drug-sensitive controls. A variety of small molecules, such as verapamil and cyclosporin A, bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. The kinetics of P-glycoprotein-mediated efflux of various anthracycline derivatives was measured in multidrug-resistant (MDR) K562 cells in the presence of verapamil. Used for the purpose were daunorubicin, idarubicin and 8-S-fluoro-idarubicin which have the same pK(a) of deprotonation equal to 8.4, but different lipophilicity, 4'-epi-2'-bromo-daunorubicin which has a lipophilicity which is comparable to that of daunorubicin but a pK(a) equal to 6.3, pirarubicin with pK(a) equal to 7.7 and lipophilicity different from that of these derivatives were used. Our data show (1) that verapamil is unable to completely block the P-glycoprotein-mediated efflux of anthracyclines and that 10% of its functionality remains even with high verapamil concentrations, (2) that the ability of verapamil to restore intracellular accumulation of anthracyclines in MDR cells depends on the kinetics of their uptake. With fast kinetics uptake, as is the case for idarubicin, 8-S-fluoro-idarubicin, 4'-epi-2'-bromo-daunorubicin and pirarubicin (which have either a low pK(a) and/or high lipophilicity), verapamil can restore in multidrug resistant cells an intracellular drug level which is comparable to that observed in sensitive cells. This is not possible when the kinetics of uptake is low as is the case for daunorubicin. Cyclosporin A is a more potent modulator and is able to fully restore daunorubicin accumulation in multidrug resistant cells. (C) 1998 Elsevier Science B.V.
引用
收藏
页码:313 / 321
页数:9
相关论文
共 43 条
[1]  
ARCECI RJ, 1993, BLOOD, V81, P2215
[2]   Co-operative, competitive and non-competitive interactions between modulators of P-glycoprotein [J].
Ayesh, S ;
Shao, YM ;
Stein, WD .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1996, 1316 (01) :8-18
[3]  
BECK WT, 1986, CANCER RES, V46, P778
[4]   PHOTOAFFINITY SUBSTRATES FOR P-GLYCOPROTEIN [J].
BECK, WT ;
QIAN, XD .
BIOCHEMICAL PHARMACOLOGY, 1992, 43 (01) :89-93
[5]   Competition of hydrophobic peptides, cytotoxic drugs, and chemosensitizers on a common P-glycoprotein pharmacophore as revealed by its ATPase activity [J].
Borgnia, MJ ;
Eytan, GD ;
Assaraf, YG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (06) :3163-3171
[6]   The effect of crown ethers, tetraalkylammonium salts, and polyoxyethylene amphiphiles on pirarubicin incorporation in K562 resistant cells [J].
Borrel, MN ;
Fiallo, M ;
Veress, I ;
GarnierSuillerot, A .
BIOCHEMICAL PHARMACOLOGY, 1995, 50 (12) :2069-2076
[7]   MOBILE IONOPHORES ARE A NOVEL CLASS OF P-GLYCOPROTEIN INHIBITORS - THE EFFECTS OF IONOPHORES ON 4'-O-TETRAHYDROPYRANYL-ADRIAMYCIN INCORPORATION IN K562 DRUG-RESISTANT CELLS [J].
BORREL, MN ;
PEREIRA, E ;
FIALLO, M ;
GARNIERSUILLEROT, A .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1994, 223 (01) :125-133
[8]   MECHANISM OF MULTIDRUG RESISTANCE [J].
BRADLEY, G ;
JURANKA, PF ;
LING, V .
BIOCHIMICA ET BIOPHYSICA ACTA, 1988, 948 (01) :87-128
[9]   IMPROVED CELLULAR ACCUMULATION IS CHARACTERISTIC OF ANTHRACYCLINES WHICH RETAIN HIGH-ACTIVITY IN MULTIDRUG RESISTANT CELL-LINES, ALONE OR IN COMBINATION WITH VERAPAMIL OR CYCLOSPORINE-A [J].
COLEY, HM ;
TWENTYMAN, PR ;
WORKMAN, P .
BIOCHEMICAL PHARMACOLOGY, 1989, 38 (24) :4467-4475
[10]  
COLEY HM, 1992, ANTI-CANCER DRUG DES, V7, P471