title: Differential effects of peroxisome proliferator-activated receptor agonists on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.
abstract: P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Therefore, identification of safe and effective MDR reversing compounds with minimal adverse side effects is an important approach in the cancer treatment. Studies show that peroxisome proliferator-activated receptor (PPARs) ligands can inhibit cell growth in many cancers. Here, we investigated the effect of different PPAR agonists include fenofibrate, troglitazone and aleglitazar on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effects of doxorubicin (DOX) following treatment with PPAR agonists on cell viability were evaluated using MTT assay and the reversal fold (RF) values. Rhodamine123 (Rh123) assays were used to determine P-gp functioning. P-gp mRNA/protein expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis after incubation with troglitazone and aleglitazar. Our results showed that troglitazone and aleglitazar significantly enhanced the cytotoxicity of DOX and decreased the RF values in K562/DOX cells, however, no such results were found for fenofibrate. Troglitazone and aleglitazar significantly down regulated P-gp expression in K562/DOX cells; in addition, the present study revealed that aleglitazar elevated intracellular accumulation of Rh123in K562/DOX cells as short-term effects, which also contribute to the reversal of MDR. These findings show that troglitazone and especially aleglitazar exhibited potent effects in the reversal of P-gp-mediated MDR, suggesting that these compounds may be effective for combination therapy strategies and circumventing MDR in K562/DOX cells to other conventional chemotherapeutic drugs.
authors.affiliation: Tabriz University of Medical Sciences Immunology Research Center Tabriz Iran.
authors.forename: B
authors.initials: B
authors.lastname: Yousefi
authors.affiliation: Tabriz University of Medical Sciences Department of Biochemistry and Clinical Laboratories, Faculty of Medicine Tabriz Iran nsamadi@ualberta.ca.
authors.forename: N
authors.initials: N
authors.lastname: Samadi
authors.affiliation: Tabriz University of Medical Sciences Immunology Research Center Tabriz Iran.
authors.forename: B
authors.initials: B
authors.lastname: Baradaran
authors.affiliation: Tabriz University of Medical Sciences Student Research Committee Tabriz Iran.
authors.forename: V
authors.initials: V
authors.lastname: Rameshknia
authors.affiliation: Tabriz University of Medical Sciences Department of Biochemistry and Clinical Laboratories, Faculty of Medicine Tabriz Iran.
authors.forename: V
authors.initials: V
authors.lastname: Shafiei-Irannejad
authors.affiliation: Tabriz University of Medical Sciences Department of Biochemistry and Clinical Laboratories, Faculty of Medicine Tabriz Iran.
authors.forename: M
authors.initials: M
authors.lastname: Majidinia
authors.affiliation: Tabriz University of Medical Sciences Drug Applied Research Center Tabriz Iran.
authors.forename: N
authors.initials: N
authors.lastname: Targhaze
authors.affiliation: Tabriz University of Medical Sciences Drug Applied Research Center Tabriz Iran nosratollahzarghami@yahoo.com.
authors.forename: N
authors.initials: N
authors.lastname: Zarghami
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D010080:Oxazoles / Q000494:pharmacology*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002839:Chromans; D010080:Oxazoles; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D013876:Thiophenes; D020112:Rhodamine 123; C542437:aleglitazar; D004317:Doxorubicin; D000077288:Troglitazone; D011345:Fenofibrate