Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diarylsulfonylurea (DSU) antitumor agents represent a new class of oncolytic compounds with an unknown, potentially novel, mechanism of action. At high concentrations of several of these agents, cytotoxicity appears to be a consequence of uncoupling of mitochondria. However, the mechanism of action at pharmacologically achievable concentrations is unknown. To further study these agents a subline of human colon carcinoma, GC3/c1, was selected for resistance to N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) (Sulofenur). This clone (designated LYC5) was stably resistant for 2 years in the absence of selection pressure and was characterized for cross-resistance to other antitumor DSU and therapeutically used oncolytic agents. LYC5 was cross-resistant to six of seven DSU analogues examined when cells were exposed to drugs for 7 days. However, the degree of resistance was inversely related to the potency of the individual DSU against the parental GC3/c1 clone. Consequently, against LYC5 cells there was a relatively narrow range for concentrations inhibiting colony formation by 50% (4-fold), compared with that in GC3/c1 cells (12-fold range). With a single exception, each DSU examined caused uncoupling of oxidative phosphorylation in isolated mitochondria at 50 microM, and data suggest that cytotoxicity in LYC5 cells may be a consequence of mitochondrial impairment. In contrast, LYC5 cells were collaterally sensitive to the mitochondrial toxins rotenone, antimycin, and oligomycin, by 11.4-, 7.2-, and 36.9-fold respectively. LYC5 cells were also collaterally sensitive to vincristine (7.7-fold), Actinomycin D (5.9-fold), and rhodamine-123 (10.5-fold), agents associated with P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). LYC5 cells were slightly more sensitive to Melphalan and doxorubicin (2.8- and 2.3-fold, respectively) but not to cisplatin or dideazatetrahydrofolic acid. Collateral sensitivity to vincristine and Actinomycin D was consistent with decreased Pgp levels in LYC5 cells. Immunohistochemical staining and Western blotting with anti-Pgp antibodies indicated an 8-fold reduction in Pgp levels in LYC5 cells, relative to expression in parental GC3/c1 cells. Consequently, association of mitochondrial toxins with resistance in MDR KB8-5 cells was examined in the presence or absence of the MDR-reversing agent verapamil. KB8-5 cells had equal or greater sensitivity, compared with parental KB3-1 cells, to rotenone, antimycin, and oligomycin and also to each DSU analogue examined. In addition, verapamil tended to have a protective effect against these mitochondrial toxins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cross-resistance to antitumor diarylsulfonylureas and collateral sensitivity to mitochondrial toxins in a human cell line selected for resistance to the antitumor agent N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea. 791 Jun 60

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.
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PMID:Separation of resistance to antitumor diarylsulfonylurea agents from collateral sensitivity to mitochondrial toxins. 860 86