Bryostatin 1 affects P-glycoprotein phosphorylation but not function in multidrug-resistant human breast cancer cells
| Autor: | Stefania Scala, Dickstein B, Regis J, Szallasi Z, Pm, Blumberg, Se, Bates |
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| Předmět: |
Rhodamines
Daunorubicin Down-Regulation Antineoplastic Agents Breast Neoplasms Bryostatins Vinblastine Drug Resistance Multiple Neoplasm Proteins Enzyme Activation Isoenzymes Lactones Drug Resistance Neoplasm Tumor Cells Cultured Humans Female ATP Binding Cassette Transporter Subfamily B Member 1 Macrolides Phosphorylation Protein Kinase C |
| Zdroj: | Europe PubMed Central |
| Popis: | The function of P-glycoprotein (Pgp), which confers multidrug resistance by active efflux of drug, is thought to be dependent on phosphorylation. Previous studies have suggested that protein kinase C (PKC) plays an important role in Pgp phosphorylation. We report here the effects of bryostatin 1, a unique PKC activator and inhibitor, on Pgp function in a multidrug-resistant MCF-7 human breast cancer subline which overexpresses PKC-alpha. Bryostatin 1 (100 nM) decreased Pgp phosphorylation after 24 h of treatment. In contrast, it did not affect Pgp function as demonstrated by the accumulation of [3H]vinblastine and rhodamine 123. We compared the effect of bryostatin 1 treatment on PKC-alpha with that of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (200 nM). 12-O-tetradecanoylphorbol-13-acetate caused translocation of PKC-alpha from the cytosol to the cell membrane after a 10-min treatment and its down-regulation after 24 h of treatment. Likewise, bryostatin 1 (100 nM) caused translocation, but only after longer treatment (1 h), and it caused down-regulation of PKC-alpha at 24 h of treatment. Thus, while the MCF-7TH cells overexpress the PKC-alpha isoform, and its down-regulation by bryostatin 1 is associated with decreased Pgp phosphorylation, these alterations do not modulate drug transport. We conclude that, while bryostatin 1 may be useful clinically because of its ability to inhibit PKC, it is not able to reverse Pgp-mediated multidrug resistance. |
| Databáze: | OpenAIRE |
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