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.
Blagosklonny
M V
MV
Medicine Branch, National Cancer Institute, Building 10, R 12N226 NIH, Bethesda, MD 20892, USA.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D034261:Epothilones; D004852:Epoxy Compounds / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D003524:Cyclosporins; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D004317:Doxorubicin; D034261:Epothilones; D004852:Epoxy Compounds; D005419:Flavonoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D017239:Paclitaxel; D010880:Piperidines; D011065:Poly(ADP-ribose) Polymerases; D011719:Pyrazines; D013844:Thiazoles; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C077990:alvocidib; C070272:valspodar; C093788:epothilone B