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Separation of resistance to antitumor diarylsulfonylurea agents from collateral sensitivity to mitochondrial toxins

LL Shu and PJ Houghton

Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105-2794, USA.

Compared with parental GC3/c1 human colon adenocarcinoma cells, which are diarylsulfonylurea (DSU)-sensitive cells, the DSU-resistant clone LYC5 demonstrates 4.2-, 12.8-, and 5.3- fold increase in sensitivity to the mitochondrial toxins rotenone, antimycin, and oligomycin, respectively. Studies with hybrids formed by fusion of parental GC3/c1 cells with LYC5 cells have indicated that resistance to antitumor DSUs and collateral sensitivity to mitochondrial toxins are recessive and therefore potentially linked. To examine this, we transfected a cDNA library from GC3/c1 cells, constructed in pcDNA3, into LYC5 cells. G418- resistant colonies were selected and further selected in a single step for resistance to rotenone (100 nm). Individual colonies (designated T5LR) were expanded and tested for sensitivity to mitochondrial toxins, antitumor DSU agents (LY195779 and LY186391) that demonstrate a 45-50- fold differential potency against GC3/c1, LYC5 cells, and the antimitotic agent vincristine. Results demonstrate that resistance to mitochondrial toxins rotenone, antimycin, and oligomycin can be transferred without conferring a DSU-sensitive phenotype. Furthermore, in T5LR clones, resistance to mitochondrial toxins was not associated with increased resistance to vincristine or increased P-glycoprotein expression, supporting the contention that resistance to these agents is independent of P-glycoprotein. Southern blot analysis of T5LR clones demonstrated unique integration sites for the neomycin phosphotransferase gene into genomic DNA in clones 4 and 9, indicating independent derivation. Analysis of clones 4, 6, and 9 with use of polymerase chain reaction demonstrated a cDNA insert of approximately 1.0 kilobase.

Volume 49, Issue 4, pp. 595-601, 04/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1996 by the American Society for Pharmacology and Experimental Therapeutics