Reversal of resistance against doxorubicin by a newly developed compound, oxalyl bis(N-phenyl)hydroxamic acid in vitro

A drug-resistant cell line (EAC/Dox) was developed by repeated exposure of Ehrllch ascltes carcinoma cells to Doxorubicin (Dox) In vivo In male albino Swiss mice (6-8 weeks old). The weekly l.p. Injections of Dox to mice (2 or 4 mg/kg/week for 4 months) gave rise to Dox-reslstant cell line EAC/Dox, which displayed typical multldrug resistant (MDR) features of cross-resistance to a number of structurally and functionally unrelated drugs like doxorubicin, vlnblastlne and clsplatln. Moreover, the EAC/Dox cell line had lower drug accumulation than drug-sensitive (EAC/S) cells. Study of Western blots and Immunofluorescence revealed that P-glycoproteln 170 kDa (P-gp) was absent In EAC/Dox cells. The drug resistance appeared to be due to the presence of a higher level of reduced glutathlone (GSH) and glutathlone S-transferase (GST) In EAC/Dox cells than In drug-sensitive (EAC/S) cells. The two structurally similar hydroxamic acid derivatives, I.e. oxalyl bls(N-phenyl)hydroxamlc acid (X1) and succlnyl bis(N-phenyl)hydroxamlc acid (X2), having very low In vitro toxlclty (ICso value 250 /ig/ ml), were Investigated for their efficacy to reverse MDR. The compound X1 was able to reverse the effect of MDR and reduce GST In EAC/Dox cells. The compound X2 had no ability to reverse the effect of MDR. Further study on the mechanism of glutathlone depletion and the resistance modifying property of X1 on other cell lines Is warranted. [© 1998 Llpplncott Williams & Wllklns.]