The role of a novel copper complex in overcoming doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo.
One of the important pathways of resistance to anthracyclines is governed by elevated levels of glutathione (GSH) in cancer cells. Resistant cells having elevated levels of GSH show higher expression of multidrug-resistant protein (MRP); the activity of glutathione S-transferases (GSTs) group of enzymes have also been found to be higher in some drug-resistant cells. The general mechanism in this type of resistance seems to be the formation of conjugates enzymatically by GSTs, and subsequent efflux by active transport through MRP (MRP1-MRP9). MRPs act as drug efflux pump and can also co-transport drugs like doxorubicin (Dox) with GSH. Depletion of GSH in resistant neoplastic cells may possibly sensitize such cells, and thus overcome multidrug resistance (MDR). A number of resistance modifying agents (RMA) like DL-buthionine (S, R) sulfoxamine (BSO) and ethacrynic acid (EA) moderately modulate resistance by acting as a GSH-depleting agent. As most of the GSH-depleting agents have dose-related toxicity, development of non-toxic GSH-depleting agent has immense importance in overcoming MDR. The present study describes the resistance reversal potentiality of novel copper complex, viz., copper N-(2-hydroxy acetophenone) glycinate (CuNG) developed by us in Dox-resistant Ehrlich ascites carcinoma (EAC/Dox) cells. CuNG depletes GSH in resistant (EAC/Dox) cells possibly by forming conjugate with it. Depletion of GSH results in higher Dox accumulation that may lead to enhanced rate of apoptosis in EAC/Dox cells. In vivo studies with male Swiss albino mice bearing ascitic growth of EAC/Dox showed tremendous increase in life span (treated/control, T/C = 453%) for the treated group with apparent regression of tumor. Resistance to Dox in EAC/Dox cells is associated with over expression of GST-P1, GST-M1 (enzymes involved in phase II detoxification) and MRP1 (a transmembrane ATPase efflux pump for monoglutathionyl conjugates of xenobiotics). CuNG causes down regulation of all these three proteins in EAC/Dox cells. The effect of CuNG as RMA is better than BSO in many aspects.
Majumder
S
S
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700026, India.
Dutta
P
P
Mookerjee
A
A
Choudhuri
S K
SK
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003300:Copper / Q000494:pharmacology*; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D051379:Mice
D000970:Antineoplastic Agents; D003300:Copper; D004317:Doxorubicin; D005982:Glutathione Transferase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione