title: Chabamide induces cell cycle arrest and apoptosis by the Akt/MAPK pathway and inhibition of P-glycoprotein in K562/ADR cells.
abstract: One of the major mechanisms of multidrug resistance in cancer therapy is the overexpression of P-glycoprotein (P-gp). Chabamide, a dimeric alkaloid isolated from Piper chaba Hunter, shows antimalarial, antituberculosis, and cytotoxic activities. However, its mechanism of action has not been elucidated. In this study, the molecular mechanism underlying the cytotoxicity and downregulation of P-gp expression by chabamide in adriamycin-resistant human leukemia cells (K562/ADR) was clarified. Results show that chabamide inhibited the growth of K562/ADR cells in a dose-dependent and time-dependent manner, and significantly inhibited cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious increase in p21 and decrease in cyclin D1 and CDK2/4/6 protein expression. Moreover, chabamide could regulate the changes in the mitochondrial membrane potential, increase the expression of apoptosis-related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl-2, caspase-9, caspase-3, PARP-1, and p-Akt. In addition, we found that JNK, ERK1/2, and p38 were regulated by chabamide in K562/ADR cells. Further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P-gp expression. Therefore, chabamide-induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P-gp. These results provide a biochemical basis for possible clinical applications of chabamide in the treatment of leukemia.
authors.affiliation: aDepartment of Pharmaceutical Engineering, School of Pharmaceutical Engineering and Life Science, Changzhou University, Jiangsu bKey Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Qianhui
authors.initials: Q
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Kun
authors.initials: K
authors.lastname: Hu
authors.forename: Kun
authors.initials: K
authors.lastname: Wei
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D010880:Piperidines; D017382:Reactive Oxygen Species; C469492:chabamide; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases