Medicines available to the patients with severe blood diseases like aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are very limited. The idea of improvement the quality of blood cells with small molecules may give a new opportunity to cure AA and hope to reverse PNH. Our proposal is based on discovery of drugs (TCC1 and TCC2) which improve performance of blood stem cells by increasing their life span. We hypothesize that the unique biological activity of these agents can already be used in clinic to treat AA and PNH by restoration the function of damaged/exhausted blood stem cells. Such effects may help to alleviate diseases and accelerate recovery of normal blood in patients with AA or PNH. The objective of this study is preclinical testing of the identified drugs to enhance the biologic effects on blood stem cells in laboratory settings. In sum, this project represents early preclinical study investigations in a clinically important field of AA and PNH with a prospect of direct translation toward development of new therapies.
An anti-aging drug screen yielded violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as its top two hits. These lead compounds extended replicative life span of normal human cells in a dose-dependent manner. Both drugs prolonged the availability of HSC, when we tested the effects on these drugs on hematopoietic stem cells (HSC) derived from normal bone marrow or from the patients diagnosed with different degree of aplastic anemia. The exact mechanism of action was identified for these drugs. VA participates in non-enzymatic electron transfers from NAD(P)H to oxidized glutathione or peroxides. N2N1 transfers electrons from NAD(P)H to cytochrome c or CoQ10 via NAD(P)H dehydrogenase (quinone) 1 (NQO1). Our results indicate that pharmacologic manipulation of NQO1 activity via redox catalysts may reveal clues as to the mechanisms of HSC maintenance, senescence and, aging under physiologic and pathologic conditions.