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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A030
Multidrug-resistance (MDR) is a major limitation to chemotherapeutic
treatment of cancer. MDR, conferred by overexpression of P-glycoprotein (Pgp)
and/or the multidrug-resistance associated protein (MRP), is characterised
by a decreased cellular drug accumulation due to an enhanced drug efflux.
In the present study we have examined phosphorylation properties of Pgp
and MRP. Both proteins are probably phosphorylated by protein kinase C
(PKC) and/or tyrosine kinase (Tyr K). The efficacy of genestein (GNST),
CGP57148B (CGP) (inhibitors of Tyr K) and GF109203X (GFX) (inhibitor of
PKC) on the sensitivity and nuclear accumulation of daunorubicine (DNR) was
examined using K562 cells lines overexpressing MRP (KH30) and Pgp (KH300).
Nuclear accumulation of DNR was carried out using microspectrofluorometry
confocal laser. We show that nuclear accumulation and cytotoxicity of DNR
were increased in KH30 cells in presence of GNST, CGP and GFX. CGP and GFX
have a moderate effect on modulation of MDR in KH300 cells. GNST was unable
to increase the DNR nuclear accumulation and sensitivity of these cells.
These findings suggested that MRP protein is highly phosphorylated by tyr K
and PKC. In KH300 cells, CGP and GFX probably interact with Pgp directly.
This result- does not support the concept of a major contribution of tyr K
and PKC to a Pgp-associated MDR. Finally, GNST, GFX and CGP might be a useful
for discrimination between Pgp and MRP phenotypes.
Inhibition of Tyrosine Kinase and Protein Kinase C Sensitize Tumor Cells
Overexpressing MRP But Not PGP
Benderra Z, Morjani H, Manfait M
UFR de Pharmacie, IFR 53, Unité Médian, Reims CEDEX, France