TY - JOUR
T1 - A thalidomide–hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes
AU - Lanaro, Carolina
AU - Franco-Penteado, Carla F.
AU - Silva, Fabio H.
AU - Fertrin, Kleber Y.
AU - dos Santos, Jean Leandro
AU - Wade, Marlene
AU - Yerigenahally, Shobha
AU - de Melo, Thais R.
AU - Chin, Chung Man
AU - Kutlar, Abdullah
AU - Meiler, Steffen E.
AU - Costa, Fernando Ferreira
N1 - Funding Information:
This work was supported by grant 2008/57441-0 from the São Paulo Research Foundation (FAPESP) and grant 558531/2008-3 from the National Council for Scientific and Technological Development (CNPq) .
Publisher Copyright:
© 2018 ISEH – Society for Hematology and Stem Cells
PY - 2018/2
Y1 - 2018/2
N2 - Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties.
AB - Fetal hemoglobin (HbF) induction by hydroxyurea (HU) therapy is associated with decreased morbidity and mortality in sickle cell anemia (SCA) patients, but not all patients respond to or tolerate HU. This provides a rationale for developing novel HbF inducers to treat SCA. Thalidomide analogs have the ability to induce HbF production while inhibiting the release of tumor necrosis factor-alpha. Molecular hybridization of HU and thalidomide was used to synthesize 3- (1,3-dioxoisoindolin-2-yl) benzyl nitrate (compound 4C). In this study, we show that compound 4C increases HbF production in a transgenic SCA mouse model and reduces the production of pro-inflammatory cytokines by SCA mouse monocytes cultured ex vivo. Therefore, compound 4C is a novel drug designed to treat SCA with a unique combination of HbF-inducing and anti-inflammatory properties.
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U2 - 10.1016/j.exphem.2017.10.003
DO - 10.1016/j.exphem.2017.10.003
M3 - Article
C2 - 29108926
AN - SCOPUS:85036647241
SN - 0301-472X
VL - 58
SP - 35
EP - 38
JO - Experimental Hematology
JF - Experimental Hematology
ER -