Abstract 4255: Natural product ginger promotes hematopoietic recovery

Abstract

Abstract Introduction Pathological anemia is a hematologic disorder with a decrease in the number of circulating erythrocytes, commonly associated with cancer chemotherapy and renal disease. The only approved agents available to treat anemia are erythropoietin (EPO) and its biologic derivatives. Unfortunately, EPO therapy elicits unwanted side-effects, including life-threatening cardiovascular complications. In addition, EPO therapy is expensive and must be delivered by injection, warranting the development of a more cost effective and non-peptide alternative for the treatment of anemia. Erythropoiesis, the process by which red blood cells differentiate, takes place in mesodermal cells during “primitive” hematopoiesis and in the aorta-gonad-mesonephros region (hemogenic endothelium) during “definitive” hematopoiesis; these processes are conserved in humans, mice and zebrafish. Methods and Results Here, we used gata1:dsRed transgenic zebrafish embryos to investigate the hematopoietic effect of a natural product, ginger, and we identified its bioactive component, 10-gingerol (10-G). Using whole-mount in situ hybridization, we confirmed that ginger or 10-G promote gata1 expression in erythrocytes as well as the expression of the hematopoietic stem cell markers cmyb and scl. Using an acute hemolytic zebrafish model and video microscopy to quantitate the number of circulating erythrocytes in the dorsal aorta, we demonstrated that ginger and 10-G can promote the hematopoietic recovery (Student's t-test, N=25 embryos per group; p<9.4x10−6). In addition, ginger treatment can also promote the differentiation of erythrocytes from a mouse erythroblast cell line. Mechanistically, using whole-mount in situ hybridization we demonstrated that ginger and 10-G induced bmp7a and bmp2b expression, as well as the downstream bmp effectors, gata2 and eve1, in zebrafish embryos. To provide further evidence that the hematopoietic effect of ginger is mediated via the Bmp/Smad signaling pathway, we demonstrated that a bmp antagonist, dorsomorphin, can abolish the effect of ginger or 10-G in hematopoietic recovery in the zebrafish anemia model. Future study will extend the hematopoietic effect of ginger in CD-1 mice. Acute hemolytic anemia will be produced by treating mice with phenylhydrazine for 1 or 2 days. Hematocrit, hemoglobin, and erythocytes levels will be determined. The results of the initial studies of CD-1 mice with ginger will be presented. Conclusions Our study using the zebrafish model provides a foundation to evaluate ginger and its bioactive components in hematopoiesis and demonstrated that the molecular mechanism is mediated through bmp signaling pathway. This finding provides insight for future study of the effect of ginger and its bioactive components in hematopoiesis in mammalian models which will lead to development of novel erythropoiesis promoting agents to treat anemia commonly associated with cancer chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4255. doi:1538-7445.AM2012-4255