3,6-Dibromocarbazole Piperazine Derivatives of 2-Propanol as First Inhibitors of Cytochrome <i>c</i> Release via Bax Channel Modulation

Bombrun, Agnès; Gerber, Patrick; Casi, Giulio; Terradillos, Olivier; Antonsson, Bruno; Halazy, S.

doi:10.1021/jm034107j

Cited by 87 publications

(90 citation statements)

References 9 publications

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“…We used the following compounds to modulate aminoglycoside-induced hair cell death: the Bax channel blocker (±)-1-(3,6-dibromocarbazol-9-yl)-3-piperazin-1-yl-propan-2-ol, bis TFA (Bombrun et al 2003), the p53 inhibitors pifithrin-α (PFTα) (Komarov et al 1999;Endo et al 2006) and pifithrin-μ (PFTμ) (Strom et al 2006), and the Mdm2 inhibitor nutlin-3a (Vassilev et al 2004). All inhibitors were purchased from EMD Millipore (Darmstadt, Germany) and dissolved in DMSO.…”

Section: Drug Treatmentsmentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

100

116

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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Section: Drug Treatmentsmentioning

confidence: 99%

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

100

116

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“…A series of 3,6-dibromocarbazole piperazine derivatives of 2-propanol that suppress Bax have been described, providing a potential starting point for future attempts to optimize compound potency. 105 Using NMR-based strategies, compounds have also been synthesized that bind to and suppress the MDP agonist Bid, 106 evidently stabilizing the inactive conformation of this MDP-activating protein. Given that bid knockout mice are protected from cell loss in several disease models, including stroke and hepatitis, 107,108 chemical inhibitors of MDP agonists could be useful for reducing tissue injury in certain disease scenarios.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

2006

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Bcl-2-family proteins are central regulators of cell life and death. At least three major classes of Bcl-2-family proteins have been delineated, including proapoptotic proteins that contain several conserved regions of sequence similarity (termed 'multidomain'). In mammals, the multidomain proteins (MDPs) of the Bcl-2 family include Bax, Bak, and Bok. The founding member of the MDP group of Bcl-2-family proteins was discovered by Stanley Korsmeyer and co-workers, initiating an exciting area of cell death research. The status of current knowledge about the mechanisms and functions of MDPs is reviewed here, and some areas for future research are outlined. Therapeutic opportunities emerging from a growing understanding of MDPs with respect to their threedimensional structures, biochemical actions, and roles in disease raise hopes that the foundation of basic research laid by Korsmeyer and others will eventually be translated into clinical benefits, leaving a legacy that benefits the world for many decades.

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“…3,6-Dibromocarbazole piperazine derivatives of 2-propanol were developed as the first small molecule modulators of BAX-induced mitochondrial and liposomal release activity. 139 Subsequently, a small molecule screen using a BAX-induced liposomal release assay identified two additional BAX channel blockers. 140 The Bax channel inhibitors Bci1 and Bci2 prevented cytochrome c release from mitochondria and protected cells from apoptosis in vitro at micromolar dosing.…”

Section: Neutralizing the Proapoptoticsmentioning

confidence: 99%

BCL-2 in the crosshairs: tipping the balance of life and death

Walensky¹

2006

Cell Death Differ

225

175

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The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

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3,6-Dibromocarbazole Piperazine Derivatives of 2-Propanol as First Inhibitors of Cytochrome c Release via Bax Channel Modulation

Cited by 87 publications

References 9 publications

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

BCL-2 in the crosshairs: tipping the balance of life and death

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