title: Guggulsterone of Commiphora mukul resin reverses drug resistance in imatinib-resistant leukemic cells by inhibiting cyclooxygenase-2 and P-glycoprotein.
abstract: The purpose of this study was to investigate the effects of guggulsterone on cyclooxygenase-2 and P-glycoprotein mediated drug resistance in imatinib-resistant K562 cells (K562/IMA). MTT cytotoxicity assay, flow cytometry, western blot analysis, and ELISA were performed to investigate the anti-proliferative effect, the reversal action of drug resistance, and the inhibitory effect on cyclooxygenase-2, P-glycoprotein, BCR/ABL kinase, and PGE2 release in K562/IMA cells by guggulsterone. The results showed that co-administration of guggulsterone resulted in a significant increase in chemo-sensitivity of K562/IMA cells to imatinib, compared with imatinib treatment alone. Rhodamine123 accumulation in K562/IMA cells was significantly enhanced after incubation with guggulsterone (60, 120 μM), compared with untreated K562/IMA cells (p<0.05). When imatinib (1 μM) was combined with guggulsterone (60, 120 μM), the mean apoptotic population of K562/IMA cells was 15.47% and 24.91%. It was increased by 3.82 and 6.79 times, compared with imatinib (1 μM) treatment alone. Furthermore, guggulsterone had significantly inhibitory effects on the levels of cyclooxygenase-2, P-glycoprotein and prostaglandin E2. However, guggulsterone had little inhibitory effect on the activity of BCR/ABL kinase. The present study indicates guggulsterone induces apoptosis by inhibiting cyclooxygenase-2 and down-regulating P-glycoprotein expression in K562/IMA cells.
authors.affiliation: Department of Clinical Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: xuhongbin@tongji.edu.cn.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Lu-Zhong
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: Department of Clinical Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xia-Ping
authors.initials: XP
authors.lastname: Mao
authors.affiliation: Department of Clinical Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D029744:Commiphora / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D010879:Piperazines / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D052246:Cyclooxygenase 2 Inhibitors; D010879:Piperazines; D011282:Pregnenediones; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C023617:pregna-4,17-diene-3,16-dione; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D016044:Fusion Proteins, bcr-abl; D015232:Dinoprostone
keywords: Commiphora mukul; Cyclooxygenase-2; Guggulsterone; Imatinib resistant; K562/IMA cells; P-glycoprotein