P‐glycoprotein‐mediated efflux of hydroxyrubicin, a neutral anthracycline derivative, in resistant K562 cells

FEBS Letters

Fiallo, Marina¹  Borrel, Marie-Nicole¹  Priebe, Waldemar²  Garnier-Suillerot, Arlette¹ 

[1] Laboratoire de Chimie Bioinorganique (LPCB URA 198 CNRS), Université Paris Nord, 74 rue Marcel Cachin, Bobigny 93012, France;The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA

关键词: Multidrug resistance;    P-Glycoprotein;    Doxorubicin;    Michaelis constant;    MDR;    multidrug resistance;    Dox;    doxorubicin;    OH-Dox;    hydroxyrubicin;    P-gp;    P-glycoprotein;   

DOI  :  10.1016/0014-5793(94)01282-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Hydroxyrubin (OH-Dox), a neutral doxorubicin derivative that is only slightly cross-resistant to doxorubicin (Dox), can be actively pumped out of resistant K562 cells by P-glycoprotein (P-gp). This efflux is saturable and can be inhibited by verapamil. The Michaelis constant is equal to 2 ± 0.5 μM. However, the efficiency of P-gp in pumping out the drugs is 2.5 times less for OH-Dox than for Dox. This shows that in order to be pumped out by P-gp a molecule does not necessarily have to have a basic center. The mean influx coefficient for the drug is 5 times higher for OH-Dox than for Dox. In conclusion, the degree of resistance of analogs is related not only to their ability to be recognized and transported by P-gp but also, and probably essentially, to their kinetics of uptake. Both parameters have to be taken into account in the rational design of new compounds capable of overcoming multidrug resistance.

【 授权许可】

Unknown