HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells

Skommer, Joanna; Wlodkowic, Donald; Mättö, Mikko; Eray, Mine; Pelkonen, Jukka

doi:10.1016/j.leukres.2005.08.022

Cited by 220 publications

(89 citation statements)

References 40 publications

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“…These results suggest that, like other BH3 mimetics (5,13,14), obatoclax can potentiate the effects of traditional chemotherapy and may offer a therapeutic advantage in combination with other targeted agents.…”

Section: Resultsmentioning

confidence: 79%

Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)

Konopleva¹,

Watt²,

Contractor³

et al. 2008

Cancer Research

246

244

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In this study, we investigated the mechanism of apoptosis induction of obatoclax (GX15-070), a novel Bcl-2 homology domain-3 (BH3) mimetic, in acute myeloid leukemia (AML) cell lines and primary AML samples. Obatoclax inhibited cell growth of HL-60, U937, OCI-AML3, and KG-1 cell lines. Apoptosis induction contributed to the observed antiproliferative effects at concentrations of this agent that mirror its affinity for antiapoptotic Bcl-2 proteins. We show that obatoclax can promote the release of cytochrome c from isolated leukemia cell mitochondria and that apoptosis induced by this agent is preceded by the release of Bak from Mcl-1, liberation of Bim from both Bcl-2 and Mcl-1, and the formation of an active Bak/Bax complex. Notably, apoptosis was diminished, but not fully prevented, in the absence of Bak/Bax or Bim, suggesting that obatoclax has additional targets that contribute to its cytotoxicity. At growth inhibitory doses that did not induce apoptosis or decrease viability, obatoclax induced an S-G 2 cell-cycle block. Obatoclax induced apoptosis in AML CD34+ progenitor cells with an average IC 50 of 3.59 F 1.23 Mmol/L although clonogenicity was inhibited at concentrations of 75 to 100 nmol/L. Obatoclax synergized with the novel BH3 mimetic ABT-737 to induce apoptosis in OCI-AML3 cells and synergistically induced apoptosis in combination with AraC in leukemic cell lines and in primary AML samples. In conclusion, we show that obatoclax potently induces apoptosis and decreases leukemia cell proliferation and may be used in a novel therapeutic strategy for AML alone and in combination with other targeted agents and chemotherapeutics. [Cancer Res 2008;68(9):3413-20]

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Section: Resultsmentioning

confidence: 79%

Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)

Konopleva¹,

Watt²,

Contractor³

et al. 2008

Cancer Research

246

244

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“…To inhibit caspase-dependent cell death induced by CD95 cross-linking and HA14-1 in HF1A3 and HF4.9 cells, respectively, cells were pretreated for 2 h with a pancaspase inhibitor z-VAD-fmk (Calbiochem, Cambridge, MA) as described earlier (25,27). For cell sorting, HF4.9 cells were seeded on 24-well polystyrene plates (Corning) and treated with 1 lM Dex for 24 h.…”

Section: Cell Death Inductionmentioning

confidence: 99%

“…Aliquots of probes were then stored at 220°C in the dark. After the treatment with apoptosis-or oncosis-inducing agents, cells were collected, rinsed with PBS to remove phenol red containing RPMI medium, and re-suspended in the 100 ll PBS containing selected SYTO dyes and plasma membrane permeability marker, propidium iodide (PI, Sigma, 5 lg/ml), as described earlier (25,26). Final concentrations of SYTO dyes were as follows: 100 nM (SYTO11 and SYTO13), 200 nM (SYTO12), 250 nM (SYTO16), and 500 nM (SYTO14 and SYTO15).…”

Section: Syto Probes Stainingmentioning

confidence: 99%

Towards an understanding of apoptosis detection by SYTO dyes

2007

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Background: SYTO probes are gaining momentum as reliable and easy to use markers of apoptotic cell death, but the phenomenon underlying reduced SYTO fluorescence in apoptotic cells as compared with normal cells is still not fully elucidated. Herein, we attempt to provide further insights into mechanisms of reduced SYTO16 fluorescence during apoptosis. Methods: Human follicular lymphoma cell lines were subjected to diverse apoptotic and oncotic stimuli with subsequent multiparametric flow cytometric and fluorescence imaging analysis. SYTO green (SYTO11-16), TMRM, PI, 7AAD, and Hoechst 33342 probes were applied for multivariate analysis of temporal sequence of apoptotic events. Sorting of cells differing in the level of SYTO16 fluorescence and subsequent characterization of obtained subpopulations were also performed. Results: Loss of SYTO16 fluorescence (SYTO low /PI 1 events) has been observed in cells exposed to oncotic stimuli, whereas SYTO high /PI 1 events did not prevail at any treatment scenario. We tracked similarities and discrepancies

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“…Among the different types of chromenes, we want to focus on 2-amino-3-cyano-4H-chromene scaffolds. They have received increasing attention in the last years due to the interesting biological activities that this specific family of heterocycles exhibits, such as antimicrobial [6][7][8] and antioxidant [9] activities as well as pro-apoptotic activity [10][11][12][13][14][15], conferring potential use as promising anticancer therapeutic drugs among others applications ( Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Enantioselective Organocatalyzed Synthesis of 2-Amino-3-cyano-4H-chromene Derivatives

2015

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Abstract:The structural motif that results from the fusion of a benzene ring to a heterocyclic pyran ring, known as chromene, is broadly found in nature and it has been reported to be associated with a wide range of biological activity. Moreover, asymmetric organocatalysis is a discipline in expansion that is already recognized as a well-established tool for obtaining enantiomerically enriched compounds. This review covers the particular case of the asymmetric synthesis of 2-amino-3-cyano-4H-chromenes using organocatalysis. Herein, we show the most illustrative examples of the methods developed by diverse research groups, following a classification based on these five different approaches: (1) addition of naphthol compounds to substituted α,α-dicyanoolefins; (2) addition of malononitrile to substituted o-vinylphenols; (3) addition of malononitrile to N-protected o-iminophenols; (4) Michael addition of nucleophiles to 2-iminochromene derivatives; and (5) organocatalyzed formal [4+2] cycloaddition reaction. In most cases, chiral thioureas have been found to be effective catalysts to promote the synthetic processes, and generally a bifunctional mode of action has been envisioned for them. In addition, squaramides and cinchona derivatives have been occasionally used as suitable catalysts for the substrates activation.

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HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells

Cited by 220 publications

References 40 publications

Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)

Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)

Towards an understanding of apoptosis detection by SYTO dyes

Enantioselective Organocatalyzed Synthesis of 2-Amino-3-cyano-4H-chromene Derivatives

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