Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 microM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.
Tyrosine/*analogs & derivatives/chemistry/pharmacology ; Prodrugs/chemistry/*pharmacology ; Oxidation-Reduction ; Molecular Structure ; Humans ; Histones/metabolism ; Histone Deacetylases/*antagonists & inhibitors/*classification/genetics/metabolism ; Hela Cells ; Enzyme Inhibitors/chemistry/*pharmacology ; Disulfides/chemistry/*pharmacology ; Cell Proliferation ; Biological Products/chemistry/*pharmacology ; Acetylation

Anemia is the most common hematologic finding in patients with advanced infections caused by human immunodeficiency virus (HIV) or advanced acquired immunodeficiency syndrome (AIDS). Among many etiologies of HIV-associated anemia, vitamin B12 deficiency plays an important role, mostly due to malabsorption or HIV enteropathy. We experienced a case of megaloblastic anemia caused by vitamin B12 deficiency in a male patient with an AIDS who had no structural gastrointestinal problem. He showed severe anemia, leukopenia, thrombocytopenia and suspicious neurologic manifestations such as aggravation of dementia and gait disturbance. With vitamin B12 and folate treatment, the patient's general condition and hematologic features were improved successfully.
Acquired Immunodeficiency Syndrome ; Anemia ; Anemia, Megaloblastic ; Dementia ; Folic Acid ; Gait ; HIV ; HIV Enteropathy ; Humans ; Leukopenia ; Male ; Neurologic Manifestations ; Thrombocytopenia ; Vitamin B 12 ; Vitamin B 12 Deficiency ; Vitamins