sdz-psc-833 has been researched along with benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone* in 2 studies
2 other study(ies) available for sdz-psc-833 and benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone
| Article | Year |
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Effect of PSC 833, a potent inhibitor of P-glycoprotein, on the growth of astrocytoma cells in vitro.
Malignant astrocytomas have been found to express P-glycoprotein (Pgp, mdr1 gene product). It was hypothesized that in addition to conferring multidrug resistance, Pgp is intimately associated with the development of astrocytomas. Accordingly, we studied the effect of PSC 833 (PSC, Novartis), a potent inhibitor of Pgp, on the growth of Pgp-expressing astrocytoma cells. The results showed that in all the cell lines tested, PSC (10-60 microM) inhibited the growth as well as induced cell death. Cells exposed to PSC exhibited DNA ladder characteristic of apoptosis. PSC-induced cell death could be reversed by Z-VAD-fmk, a general caspase inhibitor, indicating that PSC-induced cell death was characteristic of caspase-mediated apoptosis. These results suggest a novel therapeutic strategy in the treatment of malignant astrocytomas by inhibitors of Pgp. Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Astrocytoma; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain Neoplasms; Caspases; Cyclosporins; Cysteine Proteinase Inhibitors; Humans; Tumor Cells, Cultured | 2003 |
Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells.
Many chemotherapeutic agents induce apoptosis in tumor cells, but killing of normal cells remains a major obstacle. Development of multidrug resistance further limits chemotherapy in cancer. Here, I show that multidrug resistance can be exploited for selective killing of multidrug-resistant cells by a combination of an apoptosis-inducing agent that is not a substrate of either Pgp or MRP (e.g. flavopiridol) with a caspase inhibitor that is a substrate (e.g. Z-DEVD-fmk). In normal cells, treatment with caspase inhibitors prevented PARP cleavage, nuclear fragmentation, and cell death caused by flavopiridol or epothilone B. In contrast, Pgp- and MRP-expressing cells were not rescued by caspase inhibitors. Furthermore, reversal of drug resistance renders Pgp cells sensitive to caspase inhibitors abolishing therapeutic advantage. Thus, caspase inhibitors, that are inactive in multidrug-resistant cells, protect normal but not multidrug-resistant cells against chemotherapy, permitting selective eradication of multidrug-resistant cells. Clinical application of this approach may diminish the toxic side-effects of chemotherapy in patients with multidrug-resistant tumors. Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Boronic Acids; Bortezomib; Cell Cycle; Cell Survival; Cyclosporins; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; DNA Fragmentation; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epothilones; Epoxy Compounds; Flavonoids; Hematopoietic Stem Cells; HL-60 Cells; Humans; Jurkat Cells; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Oligopeptides; Paclitaxel; Piperidines; Poly(ADP-ribose) Polymerases; Pyrazines; Substrate Specificity; Thiazoles | 2001 |