In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins.

It has been shown recently in China that arsenic trioxide (A%03) is a very effective treatment for acute promyelocytic leukemia (APL). APL patients resistant to all-trans retinoic acid (ATRA) and conventional chemotherapy can still respond to A%03. In this study, we addressed the possible cellular and molecular mechanisms of this treatment by using NB, cells as a model. The results show that: (1) As2O3 triggers relatively specific NB, cell apoptosis at micromolar concentration, as proved by morphology, histogramic related nuclear DNA contents, and DNA gel eletrophoresis. (2) AS203 does not influence bax, bcl-x, c-myc, and p53 gene expression, but downregulates bcl-2 gene expression at both mRNA and protein levels. (3) AS203 induces a significant modulation of the PML staining pattern in NB, cells and HL60 cells. The micropunctates characteristic of PML-RARa in CUTE PROMYELOCYTIC leukemia (APL), a particuA lar subtype of acute myeloid leukemia (AML) with a distinct cytologic morphology (M, and M3 variant in FrenchAmerican-British [FAB] classification), is characterized by a specific chromosome translocation t( 15; 17), which results in the rearrangement of PML (for pogyelocytic leukemia) gene and retinoic acid receptor-a (RARa) gene and the expression of PML-RARa chimeric protein. Recently this protein has been considered to have an important role in APL Since 1988, it has been widely confirmed that all-trans retinoic acid (ATRA) can induce clinical complete remission (CR) in over 85% of APL patients by a