title: Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells.
abstract: Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents.
authors.affiliation: Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Srdic-Rajic
authors.affiliation: Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000, Belgrade, Serbia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Nikolic
authors.affiliation: Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia.
authors.forename: Milena
authors.initials: M
authors.lastname: Cavic
authors.affiliation: Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, Mihaila Petrovica Alasa 14, 11001, Belgrade, Serbia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Djokic
authors.affiliation: Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, Mihaila Petrovica Alasa 14, 11001, Belgrade, Serbia.
authors.forename: Branislava
authors.initials: B
authors.lastname: Gemovic
authors.affiliation: Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, Mihaila Petrovica Alasa 14, 11001, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Perovic
authors.affiliation: Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, Mihaila Petrovica Alasa 14, 11001, Belgrade, Serbia. Electronic address: nevenav@vinca.rs.
authors.forename: Nevena
authors.initials: N
authors.lastname: Veljkovic
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D054755:Imidazoline Receptors / Q000819:agonists* / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D000077769:Rilmenidine; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C494826:BAX protein, human; C534699:CCNB1 protein, human; D056744:Cyclin B1; D054755:Imidazoline Receptors; D010080:Oxazoles; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077769:Rilmenidine
keywords: Apoptosis; DNA damage; Imidazoline I1 receptor signaling; K562; Proliferation; Rilmenidine