sdz-psc-833 and alvocidib

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