Abstract
The mechanisms underlying the development of multidrug resistance in acute myeloid leukemia are not fully understood. Here we analyzed the expressions of mitochondrial ATPsyn-β in adriamycin-resistant cell line HL-60/ADM and its parental cell line HL-60. Meanwhile we compared the differences of mitochondrial ATPsyn-β expression and ATP synthase activity in 110 acute myeloid leukemia (AML, non-M3) patients between relapsed/refractory and those in remission. Our results showed that down-regulation of ATPsyn-β expression by siRNA in HL-60 cells increased cell viability and apoptotic resistance to adriamycin, while up-regulation of mitochondrial ATPsyn-β in HL-60/ADM cells enhanced cell sensitivity to adriamycin and promoted apoptosis. Mitochondrial ATPsyn-β expression and ATP synthase activity in relapsed/refractory acute myeloid leukemia patients were downregulated. This downregulated ATPsyn-β expression exhibited a positive correlation with the response to adriamycin of primary cells. A lower expression of ATPsyn-β in newly diagnosed or relapsed/refractory patients was associated with a shorter first remission duration or overall survival. Our findings show mitochondrial ATPsyn-β plays an important role in the mechanism of multidrug resistance in AML thus may present both a new marker for prognosis assessment and a new target for reversing drug resistance.
Highlights
Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disorder resulting from genetic alterations in normal hematopoietic stem cells
In an attempt to further determine whether mitochondrial ATPsyn-b is involved in the drug resistance of AML, especially in refractory/relapsed patients, and whether ATPsyn-b is a potential target for the reversal of AML multidrug resistance, we investigated ATPsyn-b expression and mitochondrial ATPase activity in bone marrow mononuclear cells (BMMCs) and CD34+ cells from non-M3 AML patients
It is interesting to note that HL-60/ADM cells displayed an evident lower mitochondrial ATPase activity(38.262.0 U) than HL-60 cells (132.1614.7 U), which indicated that down-regulated expression of mitochondrial ATPsyn-b and decreased ATPase activity in HL-60/ADM cells were both associated with drug resistance of leukemia cells
Summary
Acute myeloid leukemia (AML) is a clonal hematopoietic malignant disorder resulting from genetic alterations in normal hematopoietic stem cells. Chemotherapies typically result in dramatic remissions for AML, multidrug resistance (MDR) to chemotherapy still represents a major obstacle to successful treatment, especially in relapsed or refractory patients [1,2,3]. The mechanisms of MDR include ATP-binding cassette (ABC) transporter proteins, bcl-2 family, survivin family, anti-oxidants, DNA repair activity etc. Multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1) and multidrug resistancerelated protein 1 (MRP1/ABCC1), both belonging to the ABC super family of membrane-bound transporters, are two genes that are found to be highly related to multidrug resistance of leukemia cells. The exact mechanisms identified to date in leukemia multidrug resistance have not been elucidated. There is a need to discover new treatment strategies for relapsed/refractory AML patients
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
