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.
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.
Majumder
S
S
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700026, India.
Dutta
P
P
Mukherjee
P
P
Datta
E R
ER
Efferth
T
T
Bhattacharya
S
S
Choudhuri
S K
SK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D044482:Benzeneacetamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010070:Oxalates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D044482:Benzeneacetamides; D002121:Calcium Channel Blockers; D006877:Hydroxamic Acids; D009942:Organometallic Compounds; D010070:Oxalates; C515714:copper (N-2-hydroxyacetophenone)glycinate; C117053:oxalyl bis(N-phenyl)hydroxamic acid; D004317:Doxorubicin; D014700:Verapamil; D005998:Glycine