nitrophenols and entinostat

Based on promising in vitro and in vivo activity of several histone deacetylase inhibitors in Hodgkin lymphoma (HL), we investigated SNDX-275, an oral class 1 isoform-selective histone deacetylase inhibitors in HL-derived cell lines.. Proliferation and cell death were examined by MTS assay, Annexin V/propidium iodide, and fluorescence-activated cell sorting analysis. Gene and protein expression were measured by reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemical analysis. A multiplex assay was used to determine cytokines and chemokines.. SNDX-275 induced cell death in a dose- and time-dependent manner with an IC(50) at the sub- and lower micromolar range at 72 hours. At the molecular level, SNDX-275 increased histone H3 acetylation, upregulated p21 expression, and activated the intrinsic apoptosis pathway by downregulating the X-linked inhibitor of apoptosis protein. SNDX-275 downregulated expression of antiapoptotic Bcl-2 and Bcl-xL proteins without altering Mcl-1 or Bax levels. Combination studies demonstrated that two Bcl-2 inhibitors (ABT-737 and obatoclax) significantly enhanced the effect of SNDX-275. SNDX-275 modulated the level of several cytokines and chemokines, including interleukin-12 p40-70, interferon-inducible protein-10, RANTES (regulated on activation, normal T expressed and secreted), interleukin-13, interleukin-4, and thymus and activation-regulated chemokine and variably induced the cancer/testis antigen expression of MAGE-A4 and survivin in HL cell lines.. SNDX-275 has antiproliferative activity in HL cell lines, involving several mechanisms: induction of apoptosis, regulation of cytokines and chemokines, and alteration of cancer/testis antigens. Clinical investigation of SNDX-275 alone or in combination with Bcl-2 inhibitors is warranted in patients with HL. Phase 2 studies with SNDX-275 in HL are ongoing, and future clinical studies should investigate combinations with SNDX-275.

Topics: Acetylation; Apoptosis; Apoptosis Regulatory Proteins; Benzamides; Biphenyl Compounds; Boronic Acids; Bortezomib; Cyclin-Dependent Kinase Inhibitor p21; Deoxycytidine; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Gemcitabine; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Hodgkin Disease; Humans; Indoles; Lymphoma, Non-Hodgkin; Neoplasm Proteins; Nitrophenols; Piperazines; Protein Processing, Post-Translational; Pyrazines; Pyridines; Pyrroles; Sulfonamides; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein