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| REVERSAL OF MULTIDRUG RESISTANCE BY CALCIUM-CHANNEL BLOCKER SR33557 WITHOUT PHOTOAFFINITY-LABELING OF P-GLYCOPROTEIN |
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| Author(s): JAFFREZOU JP, HERBERT JM, LEVADE T, GAU MN, CHATELAIN P, LAURENT G |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 266 Issue: 29 Pages: 19858-19864 Published: OCT 15 1991 |
| Times Cited: 52 References: 50 |
| Abstract: The altered pharmacology of drugs in multidrug-resistant cells (decreased accumulation and retention) appears to be mediated by a high molecular weight integral membrane protein, called P-glycogprotein (P-gp). Agents known to reverse this pleiotropic drug resistance (chemosensitizers) have been shown to interact with P-gp; and as such, the inhibition of photoaffinity labeling by P-gp probes (such as [H-3]azidopine) has been proposed as a basis for mass screening of chemosensitizers. In this study, we provide direct evidence that a novel calcium channel blocker (SR33557), which was 4.5 times more potent in sensitizing P388/ADR cells to doxorubicin as compared to verapamil (while inducing a similar increase in uptake and decrease in efflux of [C-14]doxorubicin, did not compete for the [H-3]azidopine-binding site on P-gp, whereas verapamil did. Moreover, SR33557, which is inherently photoactivable, did not photolabel P-gp, but a 65-kDa protein did appear to be an acceptor; and this binding was displaced by diltiazem and nifedipine, but not by verapamil. Finally, the implication for the participation of a sphingomyelin/sphingosine cycle (as a potential lipid second messenger system) in the chemosensitization of P388/ADR cells was investigated. 30-mu-M SR33557 induced a 72% inhibition in acid lysosomal sphingomyelinase activity, a 5-fold increase in sphingosine levels, and a 75% inhibition in intracellular protein kinase C activity. Although no direct link is established between these observations and P-gp activity, further studies on a possible sphingosine-mediated regulation of P-gp may yield information on the involvement of this second messenger system in the action of SR33557. |
| Document Type: Article |
| Language: English |
Addresses:
1. CNRS, PHARMACOL & TOXICOL FONDAMENTALES LAB, F-31077 TOULOUSE, FRANCE
2. SANOFI RES CTR, F-31036 TOULOUSE, FRANCE
3. CHU RANGUEIL, BIOCHIM MED LAB, F-31054 TOULOUSE, FRANCE
4. SANOFI LABAZ RES CTR, B-1120 BRUSSELS, BELGIUM
5. CHU PURPAN, SERV HEMATOL, F-31400 TOULOUSE, FRANCE |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: GK667 |
| ISSN: 0021-9258 |
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