TY - JOUR
T1 - Vorinostat synergizes with antioxidant therapy to target myeloproliferative neoplasms
AU - Cardoso, Bruno A.
AU - Ramos, Teresa L.
AU - Belo, Hélio
AU - Vilas-Boas, Filipe
AU - Real, Carla
AU - Almeida, António M.
N1 - Funding Information:
We are grateful to Professor Jean Luc Villeval and Dr. Paolo Ghia for kindly donating the SET-2, UKE-1, and HS-5 cell lines we used in this study; Clemente da Silva for his technical support; and the patients and their families who generously contributed to this study. AMA receives consulting fees from Celgene and Novartis and is on the board of speakers for Bristol-Meyer Squibb, Shire, and Amgen. BAC, TLR, HB, FVB, and CR have no conflicts of interest to declare.
Publisher Copyright:
© 2019
PY - 2019/4
Y1 - 2019/4
N2 - BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role. These can be pharmacologically manipulated with histone deacetylase inhibitors (HDACIs), which have proven to be clinically effective in the treatment of MPNs but exhibit dose-limiting toxicity. The treatment of primary MPN cells with vorinostat modulates the expression of genes associated with apoptosis, cell cycle, inflammation, and signaling. The induction of this transcriptional program results in decreased cellular viability, paralleled by a decrease in levels of reactive oxygen species (ROS). In vitro manipulation of ROS levels revealed that the reduction of ROS levels promoted apoptosis. When vorinostat was combined with antioxidant agents, the apoptosis of MPN cells increased in a synergistic manner. The results described here suggest a novel and promising therapeutic strategy combining HDACIs with ROS-reducing agents to treat MPNs.
AB - BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role. These can be pharmacologically manipulated with histone deacetylase inhibitors (HDACIs), which have proven to be clinically effective in the treatment of MPNs but exhibit dose-limiting toxicity. The treatment of primary MPN cells with vorinostat modulates the expression of genes associated with apoptosis, cell cycle, inflammation, and signaling. The induction of this transcriptional program results in decreased cellular viability, paralleled by a decrease in levels of reactive oxygen species (ROS). In vitro manipulation of ROS levels revealed that the reduction of ROS levels promoted apoptosis. When vorinostat was combined with antioxidant agents, the apoptosis of MPN cells increased in a synergistic manner. The results described here suggest a novel and promising therapeutic strategy combining HDACIs with ROS-reducing agents to treat MPNs.
UR - http://www.scopus.com/inward/record.url?scp=85062807790&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2019.02.002
DO - 10.1016/j.exphem.2019.02.002
M3 - Article
C2 - 30769020
AN - SCOPUS:85062807790
SN - 0301-472X
VL - 72
SP - 60-71.e11
JO - Experimental Hematology
JF - Experimental Hematology
ER -
