HDAC inhibitors augment cytotoxic activity of rituximab by upregulating CD20 expression on lymphoma cells

Abstract

Anti-CD20 antibody rituximab is now essential for the treatment of CD20-positive B-cell lymphomas. Decreased expression of CD20 is one of the major mechanisms underlying both innate and acquired resistance to rituximab. In this study, we show that histone deacetylase (HDAC) inhibitors augment the cytotoxic activity of rituximab by enhancing the surface expression of CD20 antigen on lymphoma cells. HDAC inhibitors, valproic acid (VPA) and romidepsin, increased CD20 expression at protein and mRNA levels in B-cell lymphoma cell lines with relatively low CD20 expression levels. The VPA-mediated increase in CD20 expression occurred at 1 mM, which is clinically achievable and safe, but insufficient for inducing cell death. Chromatin immunoprecipitation assays revealed that HDAC inhibitors transactivated the CD20 gene through promoter hyperacetylation and Sp1 recruitment. HDAC inhibitors potentiated the activity of rituximab in complementdependent cytotoxic assays. In mouse lymphoma models, HDAC inhibitors enhanced CD20 expression along with histone hyperacetylation in transplanted cells, and acted synergistically with rituximab to retard their growth. The combination with HDAC inhibitors may serve as an effective strategy to overcome rituximab resistance in B-cell lymphomas.

Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation

“…9 Here we showed that VPA, at a clinically achievable concentration, 17 interacted with chemotherapeutic agents to induce caspase-independent autophagic cell death through PRKAA activation. This was observed not only in Tand B-lymphoma cell lines, but also in nude-mouse xenograft lymphoma models.…”

Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7

“…It has activity in vestibular schwannomas [18,20,21], neoplastic B-cells, ovarian cancer [22,23], prostate adenocarcinoma [24] and T-cell lymphoma [25]. In combination with immunotherapeutics, HDACis and rituximab (␣-CD20 mAb) have synergistic cytotoxic activity on NHL cells [26][27][28].…”

The Novel Orally Active Proteasome Inhibitor K-7174 Exerts Anti-myeloma Activity in Vitro and in Vivo by Down-regulating the Expression of Class I Histone Deacetylases

“…Absorbance at 450 nm was analyzed with a microplate reader, and expressed as a percentage of the value of the corresponding untreated cells (23).…”