Tumor selective G
            <sub>2</sub>
            /M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine

Xia, Wenle; Spector, Sydney; Hardy, Lys; Zhao, Sumin; Saluk, Alan; Alemane, Lourdes; Spector, Neil L.

doi:10.1073/pnas.97.13.7494

Cited by 73 publications

(43 citation statements)

References 34 publications

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“…These findings are in agreement with pharmacological studies showing that PBR ligands may modulate apoptosis 15,16,28 of hematopoietic cells as well as epithelial or hematological malignancies. 41 Taken together, these observations provide compelling evidence indicating that PBR belongs to the protein family which may interact within the mitochondrial membrane to regulate death signals leading to apoptosis.…”

Section: Discussionmentioning

confidence: 82%

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

Carayon

Casellas

et al. 2001

Cell Death Differ

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The peripheral benzodiazepine receptor (PBR) is a mitochondrial protein involved in the formation of mitochondrial permeability transition (PT) pores which play a critical role during the early events of apoptosis. PBRs are located in many tissues and are strongly expressed in the superficial layers of human epidermis. PBRs play a protective role against free radical damage and PBR ligands modulate apoptosis. To investigate the role of PBR during the early events of ultraviolet (UV)-mediated apoptosis we compared the effects of UVB on PBR-transfected Jurkat cells and their wild type counterparts devoid of any PBR expression. Results indicate that early after UVB exposure (up to 4 h), PBR-transfected cells were more resistant to apoptosis and exhibited a delayed mitochondrial transmembrane potential drop, a diminished superoxide anions production, and a reduced caspase-3 activation. Taken together these findings suggest that PBR may regulate early death signals leading to UV induced apoptosis. Cell Death and Differentiation (2001) 8, 747 ± 753.

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Section: Discussionmentioning

confidence: 82%

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

Carayon

Casellas

et al. 2001

Cell Death Differ

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“…The same cellular responses were evidenced using the reversible TSPO ligand PIGA too, but only at micromolar concentration (2.5 lM) and following 12 h cell exposure. Other TSPO reversible ligands have been reported to exert the same effect at micromolar ligand concentration [17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Both irDE-MPIGA and PIGA were effective to halve the number of viable U87MG cells after 24 h cell treatment at nanomolar and micromolar concentration, respectively.…”

Section: Discussionmentioning

confidence: 91%

“…In other drug-target systems, the drug dose causing a functional effect is usually about 100 times the drug binding affinity to its target (expressed in terms of Kd). In the case of the ligand-TSPO system, the efficacy dose of a TSPO ligand is up to 1,000-100,000 times its Kd values [17][18][19][20][21][22][23][24][25][26][27][28][29][30][32][33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

“…Classic TSPO ligands have been demonstrated to stimulate cell proliferation [11][12][13], to protect against apoptosis [14][15][16] and to facilitate apoptosis [17][18][19][20][21][22][23][24][25][26][27][28][29][30]. However, the effects of these TSPO ligands on cell death/life mechanisms may vary depending on the ligand concentration, the experimental setting and the type of cell populations.…”

Section: Introductionmentioning

confidence: 99%

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TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

et al. 2014

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Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside.

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“…As the anti-proliferative effects of PBR ligands were found in tumor cells but not in non-malignant keratinocytes (Fig. 3) or hepatocytes [30,31], PBR ligands appear to be tumor-selective agents [5,32]. The reason why PBR ligands induced growth inhibition of tumor cells but not of keratinocytes is yet unknown.…”

Section: Discussionmentioning

confidence: 98%

Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1

Sutter

Maaser

Grabowski

et al. 2004

Journal of Hepatology

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Tumor selective G ₂ /M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine

Cited by 73 publications

References 34 publications

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1

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Tumor selective G 2 /M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine

Cited by 73 publications

References 34 publications

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl-2 inhibitor HA14-1

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Tumor selective G ₂ /M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine