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)

We have shown previously that preactivated merocyanine 540 (pMC540) and merodantoin appear to mediate their cytotoxic effects via interaction with Topo II. Now, we demonstrate a correlation between DNA Topo II activity and drug-sensitive (MCF-7) and -insensitive (MDA-MB-231) breast cancer cell lines. Further studies indicate that MDA-MB-231 cells are insensitive to the cytotoxic and DNA cleavage effects of pMC540 and merodantoin. This loss of sensitivity is not associated with M(r) 170,000 P-glycoprotein over expression. However, in drug insensitive cells, the Topo II catalytic activity in crude nuclear extract was reduced two- to-three-fold and in cellular extracts was virtually absent as determined by decatenation of kDNA. Topoisomerase I activities appeared similar in extracts from MCF-7 and MDA-MB-231 cell lines. Drug-induced DNA cleavage was reduced two-to-threefold in nuclear extracts from MDA-MB-231. m-AMSA was more effective in inhibiting the decatenation activity in the nuclear extracts from MDA-MB-231 as compared to MCF-7 cells. Western blot analysis of whole-cell lysates revealed undetectable immunoreactivity of Topo II in the drug-insensitive cells. These data indicate that insensitivity of MDA-MB-231 to pMC540 and merodantoin is in part due to the reduced drug-induced formation of the cleavage complex and Topo II (170 kD) enzyme content.
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PMID:Correlation between DNA topoisomerase II activity and cytotoxicity in pMC540 and merodantoin sensitive and resistant human breast cancer cells. 776 97

The interaction of membrane-active amphiphiles with a series of MDR Chinese hamster ovary (CHO) cell lines was investigated. Cross-resistance to cationic amphiphiles was observed, which was effectively sensitised by verapamil. MDR cells showed collateral sensitivity to polyoxyethylene amphiphiles (Triton X-100/Nonidet P-40), which reached a maximum at 9-10 ethylene oxide units. Resistant lines were also highly collaterally sensitive (17-fold) to dibutylphthalate. mdrl transfectants showed cross-resistance to cationic amphiphiles, but no collateral sensitivity to nonionic species. Triton X-100/Nonidet P-40 inhibited 3H-azidopine photoaffinity labelling at low concentrations, perhaps reflecting a specific interaction with P-glycoprotein. Further investigation of the molecular basis of collateral sensitivity revealed that association of 3H-Triton X-100 with MDR cells reached steady state levels rapidly, and occurred by a non-mediated mechanism. The equilibrium level of X-100 uptake was inversely related to drug resistance. Collateral sensitivity is thus not a result of decreased Triton X-100 association with the cell. The fluorescent probe merocyanine 540 was used to examine the MDR plasma membrane microenvironment for physicochemical changes. Increasing levels of drug resistance correlated with a progressive shift in the mean cell fluorescence to lower levels, which suggests that the packing density in the outer leaflet of MDR cells is increased relative to that of the drug-sensitive parent.
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PMID:Interaction of multidrug-resistant Chinese hamster ovary cells with amphiphiles. 834 89