HDAC INHIBITION SYNERGIZES WITH ANTIOXIDANT THERAPY TO TARGET MYELOPROLIFERATIVE NEOPLASMS
(Abstract release date: 05/19/16)
EHA Library. M Almeida A. 06/09/16; 132886; E1337
Prof. Dr. António M Almeida
Contributions
Contributions
Abstract
Abstract: E1337
Type: Eposter Presentation
Background
The BCR-ABL-negative myeloproliferative neoplasms (MPN) are a group of heterogeneous hematological diseases with constitutive JAK-STAT pathway activation. However, despite the recent advances in unravelling disease etiology (JAK2 activating mutations), there is still no curative treatment outside bone marrow transplantation. Epigenetic alterations, like histone acetylation, play pivotal roles in the pathogenesis of several hematological malignancies, including MPN. Preliminary data showed that histone deacetylase inhibitors (HDACis) promoted in cell death and growth arrest of myeloid neoplastic cells in vitro. Importantly, HDACis have proven efficacy in clinical practice, producing remissions and increasing the overall survival in hematological malignancies. HDAC inhibition has also produced results in MPN patients, an effect severely limited by toxicity.
Aims
In order to explore the mechanism of action of HDACis in MPN, we analyzed the impact of HDACi in the cellular biology of MPN cell lines and primary bone marrow cells.
Methods
Primary MPN cells were obtained from bone marrow samples at diagnosis following informed consent. SET2, HEL and UKE-1 MPN cell lines were used. Both primary cells and cell lines were incubated with the different pharmacological reagents and at different time points, the cells were stained for Apoptosis and Reactive Oxygen Species (ROS) for detection by Flow Cytometry.
Results
Vorinostat decreased cellular viability in primary MPN cells, particularly affecting the monocytic lineage, and this was associated with a concomitant decrease in ROS levels. In MPN cell lines we showed that a wide range of HDACi (Vorinostat, Trichostatin A, Butyric Acid and Depsipeptide) produced these effects. Interestingly, HDACi-induced apoptosis was dependent on decreased ROS levels suggesting that both events are connected and necessary for MPN cell death induced by HDACi to occur. By combining both HDACi and ROS reducing drugs (ROS production inhibitors; ROS scavengers and AntiOxidants) we were able to increase MPN cell death in a synergistic manner.
Conclusion
These results point to a promising synergistic effect of HDACi with ROS depleting drugs in the context of MPN, which must be confirmed in vivo and in the clinical setting. These combinations could improve efficacy a tolerability of these agents in MPN, opening the door to a new therapeutic alternative.
Session topic: E-poster
Keyword(s): Antioxidants, HDAC inhibitor, Myeloproliferative disorder, Reactive oxygen species
Type: Eposter Presentation
Background
The BCR-ABL-negative myeloproliferative neoplasms (MPN) are a group of heterogeneous hematological diseases with constitutive JAK-STAT pathway activation. However, despite the recent advances in unravelling disease etiology (JAK2 activating mutations), there is still no curative treatment outside bone marrow transplantation. Epigenetic alterations, like histone acetylation, play pivotal roles in the pathogenesis of several hematological malignancies, including MPN. Preliminary data showed that histone deacetylase inhibitors (HDACis) promoted in cell death and growth arrest of myeloid neoplastic cells in vitro. Importantly, HDACis have proven efficacy in clinical practice, producing remissions and increasing the overall survival in hematological malignancies. HDAC inhibition has also produced results in MPN patients, an effect severely limited by toxicity.
Aims
In order to explore the mechanism of action of HDACis in MPN, we analyzed the impact of HDACi in the cellular biology of MPN cell lines and primary bone marrow cells.
Methods
Primary MPN cells were obtained from bone marrow samples at diagnosis following informed consent. SET2, HEL and UKE-1 MPN cell lines were used. Both primary cells and cell lines were incubated with the different pharmacological reagents and at different time points, the cells were stained for Apoptosis and Reactive Oxygen Species (ROS) for detection by Flow Cytometry.
Results
Vorinostat decreased cellular viability in primary MPN cells, particularly affecting the monocytic lineage, and this was associated with a concomitant decrease in ROS levels. In MPN cell lines we showed that a wide range of HDACi (Vorinostat, Trichostatin A, Butyric Acid and Depsipeptide) produced these effects. Interestingly, HDACi-induced apoptosis was dependent on decreased ROS levels suggesting that both events are connected and necessary for MPN cell death induced by HDACi to occur. By combining both HDACi and ROS reducing drugs (ROS production inhibitors; ROS scavengers and AntiOxidants) we were able to increase MPN cell death in a synergistic manner.
Conclusion
These results point to a promising synergistic effect of HDACi with ROS depleting drugs in the context of MPN, which must be confirmed in vivo and in the clinical setting. These combinations could improve efficacy a tolerability of these agents in MPN, opening the door to a new therapeutic alternative.
Session topic: E-poster
Keyword(s): Antioxidants, HDAC inhibitor, Myeloproliferative disorder, Reactive oxygen species
Abstract: E1337
Type: Eposter Presentation
Background
The BCR-ABL-negative myeloproliferative neoplasms (MPN) are a group of heterogeneous hematological diseases with constitutive JAK-STAT pathway activation. However, despite the recent advances in unravelling disease etiology (JAK2 activating mutations), there is still no curative treatment outside bone marrow transplantation. Epigenetic alterations, like histone acetylation, play pivotal roles in the pathogenesis of several hematological malignancies, including MPN. Preliminary data showed that histone deacetylase inhibitors (HDACis) promoted in cell death and growth arrest of myeloid neoplastic cells in vitro. Importantly, HDACis have proven efficacy in clinical practice, producing remissions and increasing the overall survival in hematological malignancies. HDAC inhibition has also produced results in MPN patients, an effect severely limited by toxicity.
Aims
In order to explore the mechanism of action of HDACis in MPN, we analyzed the impact of HDACi in the cellular biology of MPN cell lines and primary bone marrow cells.
Methods
Primary MPN cells were obtained from bone marrow samples at diagnosis following informed consent. SET2, HEL and UKE-1 MPN cell lines were used. Both primary cells and cell lines were incubated with the different pharmacological reagents and at different time points, the cells were stained for Apoptosis and Reactive Oxygen Species (ROS) for detection by Flow Cytometry.
Results
Vorinostat decreased cellular viability in primary MPN cells, particularly affecting the monocytic lineage, and this was associated with a concomitant decrease in ROS levels. In MPN cell lines we showed that a wide range of HDACi (Vorinostat, Trichostatin A, Butyric Acid and Depsipeptide) produced these effects. Interestingly, HDACi-induced apoptosis was dependent on decreased ROS levels suggesting that both events are connected and necessary for MPN cell death induced by HDACi to occur. By combining both HDACi and ROS reducing drugs (ROS production inhibitors; ROS scavengers and AntiOxidants) we were able to increase MPN cell death in a synergistic manner.
Conclusion
These results point to a promising synergistic effect of HDACi with ROS depleting drugs in the context of MPN, which must be confirmed in vivo and in the clinical setting. These combinations could improve efficacy a tolerability of these agents in MPN, opening the door to a new therapeutic alternative.
Session topic: E-poster
Keyword(s): Antioxidants, HDAC inhibitor, Myeloproliferative disorder, Reactive oxygen species
Type: Eposter Presentation
Background
The BCR-ABL-negative myeloproliferative neoplasms (MPN) are a group of heterogeneous hematological diseases with constitutive JAK-STAT pathway activation. However, despite the recent advances in unravelling disease etiology (JAK2 activating mutations), there is still no curative treatment outside bone marrow transplantation. Epigenetic alterations, like histone acetylation, play pivotal roles in the pathogenesis of several hematological malignancies, including MPN. Preliminary data showed that histone deacetylase inhibitors (HDACis) promoted in cell death and growth arrest of myeloid neoplastic cells in vitro. Importantly, HDACis have proven efficacy in clinical practice, producing remissions and increasing the overall survival in hematological malignancies. HDAC inhibition has also produced results in MPN patients, an effect severely limited by toxicity.
Aims
In order to explore the mechanism of action of HDACis in MPN, we analyzed the impact of HDACi in the cellular biology of MPN cell lines and primary bone marrow cells.
Methods
Primary MPN cells were obtained from bone marrow samples at diagnosis following informed consent. SET2, HEL and UKE-1 MPN cell lines were used. Both primary cells and cell lines were incubated with the different pharmacological reagents and at different time points, the cells were stained for Apoptosis and Reactive Oxygen Species (ROS) for detection by Flow Cytometry.
Results
Vorinostat decreased cellular viability in primary MPN cells, particularly affecting the monocytic lineage, and this was associated with a concomitant decrease in ROS levels. In MPN cell lines we showed that a wide range of HDACi (Vorinostat, Trichostatin A, Butyric Acid and Depsipeptide) produced these effects. Interestingly, HDACi-induced apoptosis was dependent on decreased ROS levels suggesting that both events are connected and necessary for MPN cell death induced by HDACi to occur. By combining both HDACi and ROS reducing drugs (ROS production inhibitors; ROS scavengers and AntiOxidants) we were able to increase MPN cell death in a synergistic manner.
Conclusion
These results point to a promising synergistic effect of HDACi with ROS depleting drugs in the context of MPN, which must be confirmed in vivo and in the clinical setting. These combinations could improve efficacy a tolerability of these agents in MPN, opening the door to a new therapeutic alternative.
Session topic: E-poster
Keyword(s): Antioxidants, HDAC inhibitor, Myeloproliferative disorder, Reactive oxygen species
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