Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C
| Autor: | Clifford W. Sachs, Robert L. Fine, Steadman D. Harrison, Ahmad R. Safa |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
Cell Survival
Cell Antineoplastic Agents Breast Neoplasms Safingol Vinblastine Biochemistry Cell Line Substrate Specificity chemistry.chemical_compound Sphingosine medicine Tumor Cells Cultured Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Enzyme Inhibitors skin and connective tissue diseases Myristoylated Alanine-Rich C Kinase Substrate Molecular Biology Protein kinase C Phorbol 12 13-Dibutyrate Protein Kinase C P-glycoprotein biology Cell Membrane Daunorubicin Intracellular Signaling Peptides and Proteins Brain Membrane Proteins Proteins Affinity Labels Cell Biology Molecular biology Drug Resistance Multiple Recombinant Proteins Rats medicine.anatomical_structure chemistry Verapamil Cell culture Doxorubicin biology.protein Phorbol Phosphorylation Female medicine.drug |
| Zdroj: | The Journal of biological chemistry. 270(44) |
| ISSN: | 0021-9258 |
| Popis: | Safingol is a lysosphingolipid protein kinase C (PKC) inhibitor that competitively interacts at the regulatory phorbol binding domain of PKC. We investigated the effects of safingol on antineoplastic drug sensitivity and PKC activity of MCF-7 tumor cell lines. Safingol treatment of 32P-labeled MCF-7 WT and MCF-7 DOXR cells inhibited phosphorylation of the myristoylated alanine-rich protein kinase C substrate in both cell lines, suggesting inhibition of cellular PKC. However, only in MCF-7 DOXR cells did safingol treatment increase accumulation of [3H]vinblastine and enhance toxicity of Vinca alkaloids and anthracyclines. Drug accumulation changes in MCF-7 DOXR cells treated with safingol were accompanied by inhibition of basal and phorbol 12,13-dibutyrate-stimulated phosphorylation of P-glycoprotein (P-gp). Expression of P-gp and levels of mdr1 message in MCF-7 DOXR cells were not altered by safingol treatment alone or in combination with vinblastine. Treatment of MCF-7 DOXR cell membranes with safingol did not inhibit [3H]vinblastine binding or [3H]azidopine photoaffinity labeling of P-gp. Furthermore, safingol did not stimulate P-gp ATPase activity in membranes prepared from MCF-7 DOXR cells. We conclude that enhanced drug accumulation and sensitivity in MCF-7 DOXR cells treated with safingol are correlated with inhibition of PKC rather than competitive interference with P-gp drug binding through direct interaction with P-glycoprotein. |
| Databáze: | OpenAIRE |
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