stilbenes and Hodgkin-Disease

Resveratrol (RSV), a plant-derived stilbene, induces cell death in Hodgkin lymphoma (HL)-derived L-428 cells in a dose-dependent manner (IC50 = 27 μM, trypan blue exclusion assay). At a lower range (25 μM), RSV treatment for 48 hr causes arrest in the S-phase of the cell cycle, while at a higher concentration range (50 μM), apoptosis can be detected, with activation of caspase-3. The histone/protein deacetylase SIRT1 has been described as a putative target of RSV action in other model systems, even though its role in cancer cells is still controversial. Here we show that RSV, at both concentration ranges, leads to a marked increase in p53, while a decrease of SIRT1 expression level, as well as enzyme activity, only occurred at the higher concentration range. Concomitantly, however, treatments at both concentration ranges resulted in a marked increase in K373-acetylated p53 and lysine-acetylated FOXO3a. Immunohistochemical stainings of human lymph nodes show a preferential distribution of SIRT1 in the germinal center of the follicles while the mantle zone shows nearly no staining to few positive cells. The classical HL-affected lymph nodes show a strong positivity of the diagnostic Hodgkin Reed-Sternberg cells. Notably, both the HL-derived cell lines and the Hodgkin Reed-Sternberg cells of the affected lymph nodes derive from germinal center-derived B cells. The study of SIRT1 distribution and expression on a larger number of biopsies might disclose a novel role for this histone/protein deacetylase as therapeutic target.

Topics: Acetylation; Apoptosis; B-Lymphocytes; bcl-2-Associated X Protein; Caspase 3; Cell Growth Processes; Cell Line, Tumor; Dose-Response Relationship, Drug; Forkhead Box Protein O3; Forkhead Transcription Factors; Germinal Center; Hodgkin Disease; Humans; Lymph Nodes; Resveratrol; S Phase; Sirtuin 1; Stilbenes; Tumor Suppressor Protein p53

Prognostic models for patients with Hodgkin lymphoma are imperfect and do not allow a precise individualized therapy. A recent gene-expression profiling study, translated into a routine immunohistological test, identified genes of tumor-associated macrophages as being responsible for treatment outcome in patients with Hodgkin lymphoma. If this finding is confirmed by other investigators, it could be a major step towards personalized therapy for patients with Hodgkin lymphoma.

Topics: Clinical Laboratory Techniques; Gene Expression Profiling; Hematologic Tests; Hodgkin Disease; Humans; Macrophages; Microarray Analysis; Prognosis; Stilbenes; Treatment Outcome