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Reversal of drug resistance in P-glycoprotein-expressing T-cell acute lymphoblastic CEM leukemia cells by copper N-(2-hydroxy acetophenone) glycinate and oxalyl bis (N-phenyl) hydroxamic acid
- Source :
-
Cancer Letters . Nov2006, Vol. 244 Issue 1, p16-23. 8p. - Publication Year :
- 2006
-
Abstract
- Abstract: Multiple drug resistance (MDR) represents a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. MDR occurs at the cellular level and is multi-factorial in nature. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are now well known as an important determinant of MDR. Much effort has been devoted to develop P-gp inhibitors to modulate resistance. However, most of these resistance-modifying agents (RMA) are too toxic at the required doses. Therefore, the development of novel RMAs to overcome MDR represents a major challenge to modern cancer chemotherapy. In the present investigation, we describe the effect of oxalyl bis (N-phenyl) hydroxamic acid (OBPHA) and copper N-(2-hydroxy acetophenone) glycinate (CuNG) on multidrug-resistant P-gp-expressing CEM/ADR5000 T-cell acute lymphoblastic leukemia cells. CuNG, a known depleting agent for glutathione (GSH) and inhibitor of glutathione S-transferase (GST) and multidrug resistance-related protein 1 (MRP1), also inhibited P-gp-mediated doxorubicin accumulation and retention. The resistance-modifying effects of OBPHA were stronger than that of CuNG. Both novel RMAs overcame drug resistance more efficiently than verapamil, a well-known P-gp inhibitor. OBPHA and CuNG exposure resulted in an increased doxorubicin accumulation after 1–3h incubation by down-regulation of P-gp expression after 24h incubation. This is a clue that different mechanisms may contribute to modulation of P-gp-mediated drug resistance by these compounds. [Copyright &y& Elsevier]
- Subjects :
- *P-glycoprotein
*AROMATIC amines
*LYMPHOBLASTIC leukemia
*DRUG resistance
Subjects
Details
- Language :
- English
- ISSN :
- 03043835
- Volume :
- 244
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Cancer Letters
- Publication Type :
- Academic Journal
- Accession number :
- 22637447
- Full Text :
- https://doi.org/10.1016/j.canlet.2005.11.030