Abstract
BackgroundPediatric acute myeloid leukemia (AML) remains a challenging disease to treat even with intensified cytarabine-based chemotherapy. Histone deacetylases (HDACs) have been reported to be promising therapeutic targets for treating AML. However, HDAC family members that are involved in chemotherapy sensitivities remain unknown. In this study, we sought to identify members of the HDAC family that are involved in cytarabine sensitivities, and to select the optimal HDACI that is most efficacious when combined with cytarabine for treating children with AML.MethodologyExpression profiles of classes I, II, and IV HDACs in 4 pediatric AML cell lines were determined by Western blotting. Inhibition of class I HDACs by different HDACIs was measured post immnunoprecipitation. Individual down-regulation of HDACs in pediatric AML cells was performed with lentiviral shRNA. The effects of cytarabine and HDACIs on apoptosis were determined by flow cytometry analysis.ResultsTreatments with structurally diverse HDACIs and HDAC shRNA knockdown experiments revealed that down-regulation of both HDACs 1 and 6 is critical in enhancing cytarabine-induced apoptosis in pediatric AML, at least partly mediated by Bim. However, down-regulation of HDAC2 may negatively impact cytarabine sensitivities in the disease. At clinically achievable concentrations, HDACIs that simultaneously inhibited both HDACs 1 and 6 showed the best anti-leukemic activities and significantly enhanced cytarabine-induced apoptosis.ConclusionOur results further confirm that HDACs are bona fide therapeutic targets for treating pediatric AML and suggest that pan-HDACIs may be more beneficial than isoform-specific drugs.
Highlights
Acute myeloid leukemia (AML) accounts for one-fourth of acute leukemia in children, but is responsible for more than half of the leukemia deaths in this patient population [1]
Treatments with structurally diverse HDACIs and Histone deacetylases (HDACs) shRNA knockdown experiments revealed that downregulation of both HDACs 1 and 6 is critical in enhancing cytarabine-induced apoptosis in pediatric acute myeloid leukemia (AML), at least partly mediated by Bim
Our results further confirm that HDACs are bona fide therapeutic targets for treating pediatric AML and suggest that pan-HDACIs may be more beneficial than isoform-specific drugs
Summary
Expression Profiles of Classes I, II, and IV HDACs and HDACI Sensitivities in Pediatric AML Cell Lines. Both LBH-589 and PXD101 significantly enhanced cytarabine-induced apoptosis and proliferation inhibition (as reflected in percent decrease of live cells compared to untreated cells) of THP-1 cells compared to the other HDACIs (Figures 6A&6B) This was accompanied by cooperative induction of DNA damage by the drug combinations, as reflected by the induction of cH2AX. The drug combinations did not result in further changes for c-Myc (Figure 6C) These results further support the notion that HDACs 1 and 6 are therapeutic targets in the treatment of pediatric AML and suggest that pan-HDACIs may exhibit optimal antileukemic activities at clinically achievable concentrations when combined with cytarabine compared to class I selective-HDACIs
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.
