Bi-functional prodrugs of 5-aminolevulinic acid and butyric acid increase erythropoiesis in anemic mice in an erythropoietin-independent manner.
Anemia is a major cause of morbidity and mortality worldwide resulting from a wide variety of pathological conditions. In severe cases it is treated by blood transfusions or injection of erythroid stimulating agents, e.g., erythropoietin (Epo), which can be associated with serious adverse effects. Therefore, there is a need to develop new treatment modalities. We recently reported that treatment of erythroleukemic cells with the novel the bi-functional prodrugs of 5-aminolevulinic acid (ALA) and butyric acid (BA), AN233 and AN908, enhanced hemoglobin (Hb) synthesis to a substantially higher level than did ALA and BA individually or their mixture. Herein, we describe that these prodrugs when given orally to mice induced histone deacetylase inhibition in the kidneys, bone marrow and spleen, thus, indicating good penetrability to the tissues. In mice where anemia was chemically induced, treatment with the prodrugs increased the Hb, the number of red blood cells (RBCs) and the percentage of reticulocytes to normal levels. The prodrugs had no adverse effects even after repeated treatment at 100-200mg/kg for 50days. The lack of increased levels of Epo in the blood of mice that were treated with the prodrugs suggests that AN233 and AN908 affected the Hb and RBC levels in an Epo-independent manner. Taken together with our previous studies, we propose that the prodrugs increase globin expression by BA inhibition of histone deacetylase and elevation heme synthesis by ALA. These results support an Epo-independent approach for treating anemia with these prodrugs.
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach Tikva 49100, Israel.
Ada
A
Rephaeli
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach Tikva 49100, Israel.
Nataly
N
Tarasenko
The Hematology Branch, Hebrew University - Hadassah Medical Center, Jerusalem, Israel.
Eitan
E
Fibach
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach Tikva 49100, Israel.
Gabriela
G
Rozic
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach Tikva 49100, Israel.
Ido
I
Lubin
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Beilinson Campus, Petach Tikva 49100, Israel.
Julia
J
Lipovetsky
Chemistry Department, Bar Ilan University, Ramat Gan, Israel.
Svetlana
S
Furman
Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Zvi
Z
Malik
Chemistry Department, Bar Ilan University, Ramat Gan, Israel.
Abraham
A
Nudelman
D000107:Acetylation / Q000187:drug effects; D000622:Aminolevulinic Acid / Q000378:metabolism; D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D020148:Butyric Acid / Q000378:metabolism; D004906:Erythrocyte Count; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood / Q000494:pharmacology; D006454:Hemoglobins / Q000032:analysis; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases; D006657:Histones / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007982:Levulinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
C000617178:AN233 compound; C000617179:AN908 compound; D006454:Hemoglobins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007982:Levulinic Acids; D011355:Prodrugs; D020148:Butyric Acid; D004921:Erythropoietin; D000622:Aminolevulinic Acid; D006655:Histone Deacetylases
5-Aminolevulinic acid; Anemia; Butyric acid; Erythropoietin; Hemoglobin; Histone deacetylase inhibitors