Evaluation of the Effectiveness of an Aldehyde Inhibitor Dehydrogenases (DIMATE) on the Cell Population Leukemic or Normal Stem

Overview

Aldehyde dehydrogenases (ALDHs) are cellular enzymes responsible for detoxifying aldehyde resulting from the metabolism of endogenous and exogenous xenobiotic cellular constituents. Although ALDHs are considered to play an important role in tumorigenesis, the role of ALDH activity in cancer stem cells, and more particularly that of the acute leukemia must be specified. Several studies have shown that ALDHs are potent apoptogenic compounds on normal or cancer cells. Therefore, the cells that were damaged and their increased ALDH activity does not die by apoptosis but become highly proliferating. This result is a plausible mechanism for the "evasion of apoptosis", a characteristic shared by many cancer cells. On this basis, it is proposed an innovative approach to cancer chemotherapy through inhibition of one of the protective mechanisms against apoptosis, ie the increase in ALDH activity than cancer cells put involved in overcoming the lethal effects of damaged roads. ALDHs of inhibitors they may have immediate application as anti -cancer in vivo? The limited experimental data obtained so far on human tumor xenografts in immunodeficient mice and the absence of data on the in vivo toxicology do not allow direct passage to clinical trials. Indeed, some members of the ALDH superfamily are expressed constitutively in some vital organs they protect against the deleterious effects of xenobiotics and adverse endogenous metabolites. Consequently, if ALDHs should be inhibited, of the collateral damages for the normal cells could occur. However, when normal cells have not undergone deleterious exposure, these harmful metabolites are not or in very small quantities, which do not require high levels of ALDH activity, and therefore without harm to the inhibition of cell of these enzymes. From a hematological point of view, it seems essential to test the therapeutic index of the inhibitor of ALDH DIMATE between normal hematopoietic cells and leukemic stem. Indeed, in the pathophysiology of acute leukemia, the leukemia stem cells are of major importance because they are much more resistant to chemotherapy than more differentiated cells and thus causing the high rate of relapse observed in acute leukemia despite the high rate of complete remission often obtained. In this study, it will be tested in vitro sensitivity of the cluster of differentiation 4 and cluster of differentiation 38 (CD4/CD38) highly purified of leukemic origin or normal to the DIMATE compound. The objective will be to analyze the effects of DIMATE on the parameters of the proliferation, the apoptose, the cytokinins of secretions and the changes transcriptomic in general, in order to better define the therapeutic index of this compound and to determine all the precursory hematopoietic normals and leukaemic cellular effects. The reversible cytostatic of DIMATE effect on normal cells but its irreversible apoptotic effect on cancer cells is an advantage to try to eliminate.