nitrophenols and Hodgkin-Disease

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

With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who relapse multiple times have an extremely poor prognosis. Therefore, new agents and novel therapeutic approaches are urgently needed. Anti-apoptotic proteins such as Bcl-2 and Bcl-x have been associated with the growth and survival of Hodgkin Reed-Sternberg cells and are potential therapeutic targets. ABT-737 is a small molecule that inhibits the Bcl-2 family of apoptosis regulators. In this study, we show the concentration-dependent and time-dependent cytotoxicity of ABT-737 against cell lines derived from patients with HL. A concurrent reduction in a number of intracellular cell growth and survival related molecules, such as Bcl-2, Bcl-xl, NF-kappaB and survivin was also seen. Drug combination studies using a panel of conventional and novel therapeutic agents show that ABT-737 potentiates the activity of agents that have inherent anti-lymphoma activity and provide support for the evaluation of ABT-737 in the clinical setting.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Biphenyl Compounds; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Hodgkin Disease; Humans; Inhibitory Concentration 50; NF-kappa B; Nitrophenols; Piperazines; Prognosis; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Time Factors

Topics: Alkaline Phosphatase; Cysteamine; Hodgkin Disease; Humans; Infectious Mononucleosis; Intestines; Kinetics; Leukemia; Lymphoma; Lymphoproliferative Disorders; Multiple Myeloma; Nitrophenols; Organophosphorus Compounds; Placenta