Nilsa Rivera-Del Valle1,2,3, Tiewei Cheng1,2, Mary E Irwin1,2, Hayley Donnella1,2, Melissa M Singh1,2, Joya Chandra4,5,6. 1. Department of Pediatrics Research, Children's Cancer Hospital, The University of Texas (UT) M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Unit 853, Houston, TX, 77030, USA. 2. Center for Cancer Epigenetics, The University of Texas (UT) M. D. Anderson Cancer Center, Houston, TX, 77030, USA. 3. MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. 4. Department of Pediatrics Research, Children's Cancer Hospital, The University of Texas (UT) M. D. Anderson Cancer Center, 1515 Holcombe Blvd. Unit 853, Houston, TX, 77030, USA. jchandra@mdanderson.org. 5. Center for Cancer Epigenetics, The University of Texas (UT) M. D. Anderson Cancer Center, Houston, TX, 77030, USA. jchandra@mdanderson.org. 6. MD Anderson UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. jchandra@mdanderson.org.
Abstract
PURPOSE: Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL. METHODS: The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels of intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations were evaluated. RESULTS: Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction. CONCLUSIONS: A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin.
PURPOSE: Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL. METHODS: The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels of intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations were evaluated. RESULTS: Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction. CONCLUSIONS: A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin.
Authors: Son B Le; M Katie Hailer; Sarah Buhrow; Qi Wang; Karen Flatten; Peter Pediaditakis; Keith C Bible; Lionel D Lewis; Edward A Sausville; Yuan-Ping Pang; Matthew M Ames; John J Lemasters; Ekhson L Holmuhamedov; Scott H Kaufmann Journal: J Biol Chem Date: 2007-01-09 Impact factor: 5.157
Authors: Tait D Shanafelt; Yean K Lee; Nancy D Bone; Ann K Strege; Ven L Narayanan; Edward A Sausville; Susan M Geyer; Scott H Kaufmann; Neil E Kay Journal: Blood Date: 2004-09-23 Impact factor: 22.113
Authors: Joya Chandra; Jennifer Hackbarth; Son Le; David Loegering; Nancy Bone; Laura M Bruzek; Ven L Narayanan; Alex A Adjei; Neil E Kay; Ayalew Tefferi; Judith E Karp; Edward A Sausville; Scott H Kaufmann Journal: Blood Date: 2003-08-14 Impact factor: 22.113