title: Suberoylanilide hydroxamic acid (SAHA) overcomes multidrug resistance and induces cell death in P-glycoprotein-expressing cells.
abstract: Multidrug resistance (MDR) mediated by the ATP-dependent efflux protein P-glycoprotein (P-gp) is a major obstacle to the successful treatment of many cancers. In addition to effluxing toxins, P-gp has been shown to protect tumor cells against caspase-dependent apoptosis mediated by Fas and tumor necrosis factor receptor (TNFR) ligation, serum starvation and ultraviolet (UV) irradiation. However, P-gp does not protect against caspase-independent cell death mediated by granzyme B or pore-forming proteins (perforin, pneumolysin and activated complement). We examined the effects of the chemotherapeutic hybrid polar compound suberoylanilide hydroxamic acid (SAHA) on P-gp-expressing MDR human tumor cell lines. In the CEM T-cell line, SAHA, a histone deacetylase inhibitor, induced equivalent death in P-gp-positive cells compared with P-gp-negative cells. Cell death was marked by the caspase-independent release of cytochrome c, reactive oxygen species (ROS) production and Bid cleavage that was not affected by P-gp expression. However, consistent with our previous findings, SAHA-induced caspase activation was inhibited in P-gp-expressing cells. These data provide evidence that P-gp inhibits caspase activation after chemotherapeutic drug treatment and demonstrates that SAHA may be of value for the treatment of P-gp-expressing MDR cancers.
authors.affiliation: Cancer Immunology Division, The Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia.
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Ruefli
authors.forename: David
authors.initials: D
authors.lastname: Bernhard
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Tainton
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002860:Chromium Radioisotopes / Q000378:metabolism; D003110:Colonic Neoplasms / Q000737:chemistry / Q000473:pathology; D003574:Cytochrome c Group / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002860:Chromium Radioisotopes; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D014750:Vincristine; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases