Functional inhibition of BCL2 is needed to increase the susceptibility to apoptosis to SMO inhibitors in diffuse large B-cell lymphoma of germinal center subtype (original) (raw)
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6 Apoptosis of B-cell chronic lymphocytic leukemia cells induced
. We found that this peptide, named 072RB, induced apoptosis of B-CLL samples at a concentration that does not affect viability of peripheral and bone marrow derived lymphocytes from healthy donors. Apoptosis was demonstrated by activation of Bak and Bax, externalization of plasma membranes phosphadydilserines, appearance of hypodiploid events in DNA flow cytometry histograms and was accompanied by dissipation of the mitochondrial transmembrane potential. Before the onset of marked apoptotic signs a progressive decline of the relevant anti-apoptotic proteins Bcl-X L and Mcl-1 could be observed. The negative control peptide 072RBL94A was ineffective for B-CLL cells, supporting the sequence specificity of 072RB activity. No relationship was found between responsiveness to 072RB and Mcl-1/Bcl-X L basal levels or decrease magnitude, possibly because of the limited sample size of the study. Altogether, we demonstrate that 072RB induces significant apoptosis of B-CLL cells subsequent to Bcl-X L and Mcl-1 downregulation.
Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells
Experimental …, 2006
HA14-1 induced apoptosis with an EC 50 lower than 50 μM in 26 of the 36 CLL samples analyzed. The mean EC 50 for these sensitive patients was 23 ± 2 μM. Antimycin A induced apoptosis in 13 of the 18 CLL samples analyzed. Both HA14-1 and antimycin A induced cytochrome ...
Purpose: To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL). Experimental designs: Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Phar-macologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, in vitro and in vivo on primary cell-based murine xenograft models of DLBCL. Results: By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed in vivo using primary cell-based murine xenograft models of DLBCL. Conclusions: As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL.
Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells
Oncogene, 2010
The Hedgehog (Hh) pathway regulates cell proliferation and survival and contributes to tumorigenesis. We investigated the expression and function of this pathway in B-cell chronic lymphocytic leukemia (CLL) cells and in healthy B lymphocytes. Profiling of cognate Hh pathway members revealed reduced expression of two key Hh signaling effectors, Smoothened (SMOH) and GLI, in CLL cells, whereas transcription levels of other investigated members resembled normal B-lymphocyte levels. Examining the functional role of SMOH and GLI in cell survival, we found that CLL cells were hardly sensitive toward specific SMOH inhibition, but showed an unspecific decline in cell viability in response to high concentrations of the SMOH antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT61 reduced expression of the target gene Patched and preferentially decreased the viability of malignant cells. Specific RNA interference knockdown experiments in a CLL-derived cell line confirmed the autonomous role of GLI in malignant cell survival. GANT61-induced apoptosis in primary leukemic cells was partly attenuated by protective stromal cells, but not soluble sonic hedgehog ligand. In summary, our data show a downregulation of the classical Hh pathway in CLL and suggest an intrinsic SMOH-independent role of GLI in the ex vivo survival of CLL cells.
A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo
Cancer Cell, 2010
The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). We combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo, and was observed by X-ray crystallography and NMR to bind the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.
Apoptosis regulator BCL-2 | 63
2016
Apoptosis (programmed cell death) is required for the removal of infected, damaged or unwanted cells. Inadequate cell death is a major contributing factor to tumorigenesis, while excess cell death contributes to neurodegeneration and autoimmune diseases. Current investigations suggest the mechanisms by which Bcl-2 might pre-vent cell death. Bcl-2 family members mediate anti-apoptotic signals in a wide variety of human cell systems. Bcl-2 protein family, through its role in the regu-lation of apoptotic pathways, is possibly related to cancer pathophysiology. This review article discribes some pathways how apoptotic cell death is controlled by this protein family.