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Article ; Online: Neuroprotective effects of perflurocarbon (oxycyte) after contusive spinal cord injury.

Yacoub, Adly / Hajec, Marygrace C / Stanger, Richard / Wan, Wen / Young, Harold / Mathern, Bruce E

2013 Volume 31, Issue 3, Page(s) 256–267

Abstract: Spinal cord injury (SCI) often results in irreversible and permanent neurological deficits and long-term disability. Vasospasm, hemorrhage, and loss of microvessels create an ischemic environment at the site of contusive or compressive SCI and initiate ... ...

Abstract	Spinal cord injury (SCI) often results in irreversible and permanent neurological deficits and long-term disability. Vasospasm, hemorrhage, and loss of microvessels create an ischemic environment at the site of contusive or compressive SCI and initiate the secondary injury cascades leading to progressive tissue damage and severely decreased functional outcome. Although the initial mechanical destructive events cannot be reversed, secondary injury damage occurs over several hours to weeks, a time frame during which therapeutic intervention could be achieved. One essential component of secondary injury cascade is the reduction in spinal cord blood flow with resultant decrease in oxygen delivery. Our group has recently shown that administration of fluorocarbon (Oxycyte) significantly increased parenchymal tissue oxygen levels during the usual postinjury hypoxic phase, and fluorocarbon has been shown to be effective in stroke and head injury. In the current study, we assessed the beneficial effects of Oxycyte after a moderate-to-severe contusion SCI was simulated in adult Long-Evans hooded rats. Histopathology and immunohistochemical analysis showed that the administration of 5 mL/kg of Oxycyte perfluorocarbon (60% emulsion) after SCI dramatically reduced destruction of spinal cord anatomy and resulted in a marked decrease of lesion area, less cell death, and greater white matter sparing at 7 and 42 days postinjury. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed a significant reduced number of apoptotic cells in Oxycyte-treated animals, compared to the saline group. Collectively, these results demonstrate the potential neuroprotective effect of Oxycyte treatment after SCI, and its beneficial effects may be, in part, a result of reducing apoptotic cell death and tissue sparing. Further studies to determine the most efficacious Oxycyte dose and its mechanisms of protection are warranted.
MeSH term(s)	Animals ; Disease Models, Animal ; Fluorocarbons/therapeutic use ; Immunohistochemistry ; Motor Activity/drug effects ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Long-Evans ; Recovery of Function/drug effects ; Spinal Cord Injuries/pathology
Chemical Substances	Fluorocarbons ; Neuroprotective Agents
Language	English
Publishing date	2013-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	645092-1
ISSN	1557-9042 ; 0897-7151
ISSN (online)	1557-9042
ISSN	0897-7151
DOI	10.1089/neu.2013.3037
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Article: Radiation-induced PARP activation is enhanced through EGFR-ERK signaling.

Hagan, Michael P / Yacoub, Adly / Dent, Paul

Journal of cellular biochemistry

2007 Volume 101, Issue 6, Page(s) 1384–1393

Abstract: We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the ... ...

Abstract	We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the appearance of polyADP-ribose, the incorporation of P32-labelled NADH, and by cellular NADH. EGFR-ERK signaling was manipulated through ligand activation or signal interruption using the tyrphostin AG1478, or MEK inhibitor PD 184352. EGF activation of ERK prior to irradiation was associated with a marked increase in PARP activation and decreased survival in both cell lines. Prior inactivation of PARP protected both cell lines from the initial decrease in NAD+ and improved the survival of LNCaP cells following combined EGF and IR treatment. MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling.
MeSH term(s)	Cell Death ; Cell Line, Tumor/metabolism ; Cell Line, Tumor/radiation effects ; DNA Damage ; Enzyme Activation ; Enzyme Inhibitors/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; MAP Kinase Signaling System/physiology ; Male ; NAD/metabolism ; Nicotinamide-Nucleotide Adenylyltransferase/genetics ; Nicotinamide-Nucleotide Adenylyltransferase/metabolism ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; Prostatic Neoplasms ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Radiation, Ionizing ; Receptor, Epidermal Growth Factor/metabolism
Chemical Substances	Enzyme Inhibitors ; RNA, Small Interfering ; NAD (0U46U6E8UK) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; NMNAT1 protein, human (EC 2.7.7.1) ; Nicotinamide-Nucleotide Adenylyltransferase (EC 2.7.7.1)
Language	English
Publishing date	2007-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.21253
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Zs.A 1114: Show issues

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Article: DMC: novel celecoxib derivatives to rap cancer.

Dent, Paul / Yacoub, Adly / Grant, Steven

Cancer biology & therapy

2005 Volume 4, Issue 5, Page(s) 583–584

MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Celecoxib ; Cell Cycle Proteins/analysis ; Cell Cycle Proteins/metabolism ; Cell Proliferation/drug effects ; Cyclin A/metabolism ; Cyclin B/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Cyclooxygenase Inhibitors/pharmacology ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Neoplasm Transplantation ; Phosphorylation/drug effects ; Pyrazoles/pharmacology ; Sulfonamides/pharmacology ; Transplantation, Heterologous ; Xenograft Model Antitumor Assays
Chemical Substances	2,5-dimethylcelecoxib ; Antineoplastic Agents ; Cell Cycle Proteins ; Cyclin A ; Cyclin B ; Cyclooxygenase Inhibitors ; Pyrazoles ; Sulfonamides ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Celecoxib (JCX84Q7J1L)
Language	English
Publishing date	2005-05-10
Publishing country	United States
Document type	Comment ; Comparative Study ; Journal Article
ZDB-ID	2146305-0
ISSN	1538-4047
ISSN	1538-4047
DOI	10.4161/cbt.4.5.1794
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Zs.A 5887: Show issues

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Article ; Online: CHK1 inhibitors in combination chemotherapy: thinking beyond the cell cycle.

Dent, Paul / Tang, Yong / Yacoub, Adly / Dai, Yun / Fisher, Paul B / Grant, Steven

Molecular interventions

2011 Volume 11, Issue 2, Page(s) 133–140

Abstract: Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in ... ...

Abstract	Cellular sensing of DNA damage, along with concomitant cell cycle arrest, is mediated by a great many proteins and enzymes. One focus of pharmaceutical development has been the inhibition of DNA damage signaling, and checkpoint kinases (Chks) in particular, as a means to sensitize proliferating tumor cells to chemotherapies that damage DNA. 7-Hydroxystaurosporine, or UCN-01, is a clinically relevant and well-studied kinase activity inhibitor that exerts chemosensitizing effects by inhibition of Chk1, and a multitude of Chk1 inhibitors have entered development. Clinical development of UCN-01 has overcome many initial obstacles, but the drug has nevertheless failed to show a high level of clinical activity when combined with chemotherapeutic agents. One very likely reason for the lack of clinical efficacy of Chk1 inhibitors may be that the inhibition of Chk1 causes the compensatory activation of ATM and ERK1/2 pathways. Indeed, inhibition of many enzyme activities, not necessarily components of cell cycle regulation, may block Chk1 inhibitor-induced ERK1/2 activation and enhance the toxicity of Chk1 inhibitors. This review examines the rationally hypothesized actions of Chk1 inhibitors as cell cycle modulatory drugs as well as the impact of Chk1 inhibition upon other cell survival signaling pathways. An understanding of Chk1 inhibition in multiple signaling contexts will be essential to the therapeutic development of Chk1 inhibitors.
MeSH term(s)	Animals ; Cell Cycle/drug effects ; Cell Death/drug effects ; Checkpoint Kinase 1 ; Drug Therapy, Combination/methods ; Humans ; MAP Kinase Signaling System/drug effects ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinases/metabolism
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; Protein Kinases (EC 2.7.-) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1)
Language	English
Publishing date	2011-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2108819-6
ISSN	1543-2548 ; 1534-0384
ISSN (online)	1543-2548
ISSN	1534-0384
DOI	10.1124/mi.11.2.11
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Zs.A 5844: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Melanoma Differentiation-associated Gene 7/IL-24 Exerts Cytotoxic Effects by Altering the Alternative Splicing of Bcl-x Pre-mRNA via the SRC/PKCδ Signaling Axis.

Shapiro, Brian A / Vu, Ngoc T / Shultz, Michael D / Shultz, Jacqueline C / Mietla, Jennifer A / Gouda, Mazen M / Yacoub, Adly / Dent, Paul / Fisher, Paul B / Park, Margaret A / Chalfant, Charles E

The Journal of biological chemistry

2016 Volume 291, Issue 41, Page(s) 21669–21681

Abstract: Melanoma differentiation-associated gene 7 (MDA-7/IL-24) exhibits cytotoxic effects on tumor cells while sparing untransformed cells, and Bcl-x(L) is reported to efficiently block the induction of cell death by MDA-7/IL-24. The expression of Bcl-x(L) is ... ...

Abstract	Melanoma differentiation-associated gene 7 (MDA-7/IL-24) exhibits cytotoxic effects on tumor cells while sparing untransformed cells, and Bcl-x(L) is reported to efficiently block the induction of cell death by MDA-7/IL-24. The expression of Bcl-x(L) is regulated at the level of RNA splicing via alternative 5' splice site selection within exon 2 to produce either the pro-apoptotic Bcl-x(s) or the anti-apoptotic Bcl-x(L). Our laboratory previously reported that Bcl-x RNA splicing is dysregulated in a large percentage of human non-small cell lung cancer (NSCLC) tumors. Therefore, we investigated whether the alternative RNA splicing of Bcl-x pre-mRNA was modulated by MDA-7/IL-24, which would suggest that specific NSCLC tumors are valid targets for this cytokine therapy. Adenovirus-delivered MDA-7/IL-24 (Ad.mda-7) reduced the viability of NSCLC cells of varying oncogenotypes, which was preceded by a decrease in the ratio of Bcl-x(L)/Bcl-x(s) mRNA and Bcl-x(L) protein expression. Importantly, both the expression of Bcl-x(L) and the loss of cell viability were "rescued" in Ad.mda-7-treated cells incubated with Bcl-x(s) siRNA. In addition, NSCLC cells ectopically expressing Bcl-x(s) exhibited significantly reduced Bcl-x(L) expression, which was again restored by Bcl-x(s) siRNA, suggesting the existence of a novel mechanism by which Bcl-x(s) mRNA restrains the expression of Bcl-x(L). In additional mechanistic studies, inhibition of SRC and PKCδ completely ablated the ability of MDA-7/IL-24 to reduce the Bcl-x(L)/(s) mRNA ratio and cell viability. These findings show that Bcl-x(s) expression is an important mediator of MDA-7/IL-24-induced cytotoxicity requiring the SRC/PKCδ signaling axis in NSCLC cells.
MeSH term(s)	A549 Cells ; Alternative Splicing ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Humans ; Interleukins/genetics ; Interleukins/metabolism ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Protein Kinase C-delta/genetics ; Protein Kinase C-delta/metabolism ; Proto-Oncogene Proteins pp60(c-src)/genetics ; Proto-Oncogene Proteins pp60(c-src)/metabolism ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Signal Transduction ; bcl-X Protein/genetics ; bcl-X Protein/metabolism
Chemical Substances	BCL2L1 protein, human ; Interleukins ; RNA, Messenger ; RNA, Neoplasm ; bcl-X Protein ; interleukin-24 ; Proto-Oncogene Proteins pp60(c-src) (EC 2.7.10.2) ; PRKCD protein, human (EC 2.7.11.13) ; Protein Kinase C-delta (EC 2.7.11.13)
Language	English
Publishing date	2016-08-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.737569
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Article ; Online: The neuro-steroid, 5-androstene 3β,17α diol; induces endoplasmic reticulum stress and autophagy through PERK/eIF2α signaling in malignant glioma cells and transformed fibroblasts.

Jia, Wentao / Loria, Roger M / Park, Margaret A / Yacoub, Adly / Dent, Paul / Graf, Martin R

The international journal of biochemistry & cell biology

2010 Volume 42, Issue 12, Page(s) 2019–2029

Abstract: In this study, we identified a mechanism by which the neuro-steroid, 5-androstene 3β,17α diol (17α-AED) induces autophagy in human malignant glioma cells and transformed fibroblasts. 17α-AED treatment induced endoplasmic reticulum (ER) stress, identified ...

Abstract	In this study, we identified a mechanism by which the neuro-steroid, 5-androstene 3β,17α diol (17α-AED) induces autophagy in human malignant glioma cells and transformed fibroblasts. 17α-AED treatment induced endoplasmic reticulum (ER) stress, identified by the partial activation of an unfolded protein response in T98G, U87MG, U251MG, LN-18, LN-229 and LN-Z308 glioma cell lines. In this regard, there were increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein of 78kDa transcripts but no splicing of X-box-binding protein 1 mRNA or processing of activating transcription factor-6 in glioma cells treated with the neuro-steroid. 17α-AED induced eukaryotic translational initiation factor 2α (eIF2α) phosphorylation in glioma cells which correlated with microtubule-associated protein-light chain 3 (LC3) conversion from LC3-I to -II. In transformed murine embryonic fibroblasts (MEFs) that are deficient of eIF2α function or T98G glioma cells transfected with a dominant-negative eIF2α construct, 17α-AED induced LC3 conversion was significantly reduced as compared to control cells. Neuro-steroid treatment caused the activation of the eIF2α kinase, protein kinase-like ER kinase (PERK) but not other eIF2α kinases in glioma cells. Moreover, eIF2α phosphorylation and LC3 conversion, in response to 17α-AED treatment, was blocked in MEFs that lacked PERK activity. T98G cells transfected with a dominant-negative PERK construct exhibited an attenuated response to neuro-steroid treatment in terms of decreases in: eIF2α activation; CHOP expression; the incidence of autophagy; and cytotoxicity. These results demonstrate that ER stress is linked to 17α-AED induced autophagy by PERK/eIF2α signaling in human malignant glioma cells and transformed fibroblasts.
MeSH term(s)	Androstenediols/pharmacology ; Animals ; Autophagy/physiology ; Cell Line, Transformed ; Endoplasmic Reticulum/metabolism ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Glioma/drug therapy ; Glioma/metabolism ; Glioma/pathology ; Humans ; Immunoblotting ; Mice ; Mice, Nude ; Phosphorylation ; Signal Transduction ; Transfection ; eIF-2 Kinase/metabolism
Chemical Substances	Androstenediols ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2010-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2010.09.003
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Zs.A 431: Show issues

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Article ; Online: Histone deacetylase inhibitors interact with melanoma differentiation associated-7/interleukin-24 to kill primary human glioblastoma cells.

Hamed, Hossein A / Yacoub, Adly / Park, Margaret A / Archer, Kellie / Das, Swadesh K / Sarkar, Devanand / Grant, Steven / Fisher, Paul B / Dent, Paul

Molecular pharmacology

2013 Volume 84, Issue 2, Page(s) 171–181

Abstract: We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL-24) in invasive primary human glioblastoma multiforme (GBM) cells. Additionally, a method is ... ...

Abstract	We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL-24) in invasive primary human glioblastoma multiforme (GBM) cells. Additionally, a method is described to augment the efficacy of adenoviral delivery of mda-7/IL-24 in these cells. HDACIs synergized with melanoma differentiation-associated (MDA)-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on the expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of reactive oxygen species and Ca(2+). Quenching of reactive oxygen species and Ca(2+) blocked HDACI and MDA-7/IL-24 killing. In vivo MDA-7/IL-24 prolonged the survival of animals carrying orthotopic tumors, and HDACIs enhanced survival further. A serotype 5/3 adenovirus more effectively delivers mda-7/IL-24 to GBM tumors than a serotype 5 virus. Hence, we constructed a serotype 5/3 adenovirus that conditionally replicates in tumor cells expressing MDA-7/IL-24, in which the adenoviral early region 1A (E1A) gene was driven by the cancer-specific promoter progression elevated gene-3 [Ad.5/3 (INGN 241)-PEG-E1A-mda-7; also called Ad.5/3-CTV (cancer terminator virus)]. Ad.5/3-CTV increased the survival of mice carrying GBM tumors to a significantly greater extent than did a nonreplicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrate that HDACIs enhance MDA-7/IL-24 lethality, and adenoviral delivery of mda-7/IL-24 combined with tumor-specific viral replication is an effective preclinical GBM therapeutic.
MeSH term(s)	Adenoviridae/metabolism ; Animals ; Brain Neoplasms/drug therapy ; Brain Neoplasms/enzymology ; Brain Neoplasms/metabolism ; Brain Neoplasms/therapy ; Calcium/metabolism ; Cell Line, Tumor ; Cricetinae ; Female ; Genetic Therapy/methods ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Glioblastoma/therapy ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Interleukins/metabolism ; Membrane Proteins/metabolism ; Mice ; Mice, Nude ; Reactive Oxygen Species/metabolism ; Sphingosine N-Acyltransferase/metabolism
Chemical Substances	Histone Deacetylase Inhibitors ; Interleukins ; Membrane Proteins ; Reactive Oxygen Species ; interleukin-24 ; CERS6 protein, human (EC 2.3.1.24) ; Sphingosine N-Acyltransferase (EC 2.3.1.24) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2013-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.113.086553
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Zs.A 525: Show issues

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Article ; Online: Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in carcinoma cells.

Mitchell, Clint / Park, Margaret / Eulitt, Patrick / Yang, Chen / Yacoub, Adly / Dent, Paul

Molecular pharmacology

2010 Volume 78, Issue 5, Page(s) 909–917

Abstract: Prior studies have demonstrated that inhibition of CHK1 can promote the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylation of histone H2AX and that inhibition of poly(ADP-ribose) polymerase 1 (PARP1) can affect ... ...

Abstract	Prior studies have demonstrated that inhibition of CHK1 can promote the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and phosphorylation of histone H2AX and that inhibition of poly(ADP-ribose) polymerase 1 (PARP1) can affect growth factor-induced ERK1/2 activation. The present studies were initiated to determine whether CHK1 inhibitors interacted with PARP1 inhibition to facilitate apoptosis. Transient expression of dominant-negative CHK1 raised basal ERK1/2 activity and prevented CHK1 inhibitors from activating ERK1/2. CHK1 inhibitors modestly increased the levels of PARP1 ADP ribosylation and molecular or small-molecule inhibition of PARP1 blocked CHK1 inhibitor-stimulated histone H2AX phosphorylation and activation of ERK1/2. Stimulated histone H2AX phosphorylation was ataxia telangiectasia-mutated protein-dependent. Multiple CHK1 inhibitors interacted in a greater than additive fashion with multiple PARP1 inhibitors to cause transformed cell-killing in short-term viability assays and synergistically killed tumor cells in colony-formation assays. Overexpression of BCL-xL or loss of BAX/BAK function, but not the function of BID, suppressed CHK1 inhibitor + PARP1 inhibitor lethality. Inhibition of BCL-2 family protein function enhanced CHK1 inhibitor + PARP1 inhibitor lethality and restored drug-induced cell-killing in cells overexpressing BCL-xL. Thus, PARP1 plays an important role in regulating the ability of CHK1 inhibitors to activate ERK1/2 and the DNA damage response. An inability of PARP1 to modulate this response results in transformed cell death mediated through the intrinsic apoptosis pathway.
MeSH term(s)	Cell Death/drug effects ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Drug Synergism ; Enzyme Activation ; Histones/metabolism ; Humans ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/physiology ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism ; Signal Transduction/drug effects ; Staurosporine/analogs & derivatives ; Staurosporine/pharmacology ; Thiophenes/pharmacology ; Urea/analogs & derivatives ; Urea/pharmacology
Chemical Substances	3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide ; H2AX protein, human ; Histones ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; Thiophenes ; 7-hydroxystaurosporine (7BU5H4V94A) ; Urea (8W8T17847W) ; PARP1 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Protein Kinases (EC 2.7.-) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Staurosporine (H88EPA0A3N)
Language	English
Publishing date	2010-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.110.067199
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Article: Ionizing radiation causes a dose-dependent release of transforming growth factor alpha in vitro from irradiated xenografts and during palliative treatment of hormone-refractory prostate carcinoma.

Hagan, Michael / Yacoub, Adly / Dent, Paul

Clinical cancer research : an official journal of the American Association for Cancer Research

2004 Volume 10, Issue 17, Page(s) 5724–5731

Abstract: Purpose: Characterize the radiation response for transforming growth factor (TGF) alpha shedding in vitro and in vivo. We also report the shedding of TGF alpha by patients undergoing irradiation for hormone-refractory prostate cancer.: Experimental ... ...

Abstract	Purpose: Characterize the radiation response for transforming growth factor (TGF) alpha shedding in vitro and in vivo. We also report the shedding of TGF alpha by patients undergoing irradiation for hormone-refractory prostate cancer. Experimental design: TGF alpha levels were determined by ELISA. DU145 xenografts were established on the flanks of athymic nu/nu mice. Expression of phospho-extracellular signal-regulated kinase (ERK)1/2 and phospho-epidermal growth factor receptor (EGFR) and the DNA repair proteins XRCC1 and ERCC1 were determined by Western analyses. Results: Exposure to ionizing radiation results in a dose-dependent release of TGF alpha. Once released, TGF alpha stimulates EGFR-ERK1/2 signaling in unirradiated cells. Blockade of the EGFR with the tyrphostin AG1478 eliminates the up-regulation XRCC1 and ERCC1 by TGF alpha or irradiation. After irradiation, cells are refractory to additional transactivation of EGFR by additional irradiation for 8 to 12 hours. Irradiation during this refractory period does not increase the expression of XRCC1 or ERCC1. Ligand activation of EGFR is maintained during the refractory period. Irradiation of DU145 xenografts also results in the activation of ERK1/2, release of TGF alpha, and a similar refractory period. Ionizing irradiation also results in the release of TGF alpha for patients undergoing radiation therapy for hormone-refractory prostate cancer. Conclusions: Irradiation results in a dose-dependent increase in TGF alpha capable of enhancing the growth of DU145 xenografts. TGF alpha is also shed following radiation therapy of patients treated for hormone-refractory prostate cancer. Radiation transactivation of the EGFR produces a radio-refractory period, which lasts for several hours. During this period, additional irradiation fails to induce XRCC1, ERCC1, or additional TGF alpha release.
MeSH term(s)	Adenocarcinoma/metabolism ; Adenocarcinoma/radiotherapy ; Animals ; Blotting, Western ; Case-Control Studies ; DNA Repair ; DNA-Binding Proteins/metabolism ; Dose-Response Relationship, Radiation ; Endonucleases/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; In Vitro Techniques ; Male ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Neoplasms, Hormone-Dependent/metabolism ; Neoplasms, Hormone-Dependent/radiotherapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/radiotherapy ; Radiation, Ionizing ; Receptor, Epidermal Growth Factor/metabolism ; Transforming Growth Factor alpha/metabolism ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Up-Regulation ; Whole-Body Irradiation ; X-ray Repair Cross Complementing Protein 1
Chemical Substances	DNA-Binding Proteins ; Transforming Growth Factor alpha ; X-ray Repair Cross Complementing Protein 1 ; XRCC1 protein, human ; Xrcc1 protein, mouse ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; ERCC1 protein, human (EC 3.1.-) ; Endonucleases (EC 3.1.-) ; Ercc1 protein, mouse (EC 3.1.-)
Language	English
Publishing date	2004-09-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-04-0420
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Article ; Online: Sorafenib and HDAC inhibitors synergize to kill CNS tumor cells.

Tang, Yong / Yacoub, Adly / Hamed, Hossein A / Poklepovic, Andrew / Tye, Gary / Grant, Steven / Dent, Paul

Cancer biology & therapy

2012 Volume 13, Issue 7, Page(s) 567–574

Abstract: The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was ... ...

Abstract	The present studies were designed to determine whether the multi-kinase inhibitor sorafenib (Nexavar) interacted with histone deacetylase inhibitors to kill glioblastoma and medulloblastoma cells. In a dose-dependent fashion sorafenib lethality was enhanced in multiple genetically disparate primary human glioblastoma isolates by the HDAC inhibitor sodium valproate (Depakote). Drug exposure reduced phosphorylation of p70 S6K and of mTOR. Similar data to that with valproate were also obtained using the HDAC inhibitor vorinostat (Zolinza). Sorafenib and valproate also interacted to kill medulloblastoma and PNET cell lines. Treatment with sorafenib and HDAC inhibitors radio-sensitized both GBM and medulloblastoma cell lines. Knock down of death receptor (CD95) expression protected GBM cells from the drug combination, as did overexpression of c-FLIP-s, BCL-XL and dominant negative caspase 9. Knock down of PDGFRα recapitulated the effect of sorafenib in combination with HDAC inhibitors. Collectively, our data demonstrate that the combination of sorafenib and HDAC inhibitors kills through activation of the extrinsic pathway, and could represent a useful approach to treat CNS-derived tumors.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Benzenesulfonates/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Central Nervous System Neoplasms/enzymology ; Central Nervous System Neoplasms/genetics ; Drug Synergism ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Niacinamide/analogs & derivatives ; Phenylurea Compounds ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Sorafenib ; fas Receptor/genetics ; fas Receptor/metabolism
Chemical Substances	Antineoplastic Agents ; Benzenesulfonates ; Histone Deacetylase Inhibitors ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyridines ; fas Receptor ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87)
Language	English
Publishing date	2012-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.19771
Database	MEDical Literature Analysis and Retrieval System OnLINE

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