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Article ; Online: Sorafenib/regorafenib and lapatinib interact to kill CNS tumor cells.

Hamed, Hossein A / Tavallai, Seyedmehrad / Grant, Steven / Poklepovic, Andrew / Dent, Paul

2014 Volume 230, Issue 1, Page(s) 131–139

Abstract: The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib ... ...

Abstract	The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib interacted in a greater than additive fashion to cause tumor cell death. Tumor cells lacking PTEN, and anoikis or lapatinib resistant cells were as sensitive to the drug combination as cells expressing PTEN or parental cells, respectively. Similar data were obtained using regorafenib. Treatment of brain cancer cells with [sorafenib + lapatinib] enhanced radiation toxicity. The drug combination increased the numbers of LC3-GFP vesicles; this correlated with a reduction in endogenous LC3II, and p62 and LAMP2 degradation. Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, BCL-XL, or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 or activated mTOR was required to strongly suppress drug combination lethality. As both lapatinib and sorafenib are FDA approved agents, our data argue for further determination as to whether lapatinib and sorafenib is a useful glioblastoma therapy.
MeSH term(s)	Anoikis/drug effects ; Antineoplastic Agents/pharmacology ; Apoptosis Regulatory Proteins/genetics ; Autophagy-Related Protein 5 ; Beclin-1 ; Brain Neoplasms/drug therapy ; Brain Neoplasms/radiotherapy ; CASP8 and FADD-Like Apoptosis Regulating Protein/biosynthesis ; Caspase 9/biosynthesis ; Cell Line, Tumor ; Drug Synergism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; Fas-Associated Death Domain Protein/genetics ; Glioblastoma/drug therapy ; Humans ; Lapatinib ; Lysosomal-Associated Membrane Protein 2/metabolism ; MAP Kinase Kinase 1/biosynthesis ; Membrane Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; PTEN Phosphohydrolase/genetics ; Phenylurea Compounds/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/biosynthesis ; Pyridines/pharmacology ; Quinazolines/pharmacology ; Sorafenib ; TOR Serine-Threonine Kinases/biosynthesis ; Unfolded Protein Response/drug effects ; bcl-X Protein/biosynthesis ; bcl-X Protein/metabolism ; fas Receptor/genetics
Chemical Substances	ATG5 protein, human ; Antineoplastic Agents ; Apoptosis Regulatory Proteins ; Autophagy-Related Protein 5 ; BCL2L1 protein, human ; BECN1 protein, human ; Beclin-1 ; CASP8 and FADD-Like Apoptosis Regulating Protein ; CFLAR protein, human ; FADD protein, human ; FAS protein, human ; Fas-Associated Death Domain Protein ; LAMP2 protein, human ; Lysosomal-Associated Membrane Protein 2 ; MAP1LC3A protein, human ; Membrane Proteins ; Microtubule-Associated Proteins ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyridines ; Quinazolines ; bcl-X Protein ; fas Receptor ; Lapatinib (0VUA21238F) ; regorafenib (24T2A1DOYB) ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; MAP2K1 protein, human (EC 2.7.12.2) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2014-06-09
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	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.24689
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Article ; Online: Pazopanib and HDAC inhibitors interact to kill sarcoma cells.

Tavallai, Seyedmehrad / Hamed, Hossein A / Grant, Steven / Poklepovic, Andrew / Dent, Paul

Cancer biology & therapy

2014 Volume 15, Issue 5, Page(s) 578–585

Abstract: The present studies were to determine whether the multi-kinase inhibitor pazopanib interacted with histone deacetylase inhibitors (HDACI: valproate, vorinostat) to kill sarcoma cells. In multiple sarcoma cell lines, at clinically achievable doses, ... ...

Abstract	The present studies were to determine whether the multi-kinase inhibitor pazopanib interacted with histone deacetylase inhibitors (HDACI: valproate, vorinostat) to kill sarcoma cells. In multiple sarcoma cell lines, at clinically achievable doses, pazopanib and HDACI interacted in an additive to greater than additive fashion to cause tumor cell death. The drug combination increased the numbers of LC3-GFP and LC3-RFP vesicles. Knockdown of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, and to a lesser extent BCL-XL or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 was required to strongly suppress drug combination lethality. The drug combination inactivated mTOR and expression of activated mTOR strongly suppressed drug combination lethality. Treatment of animals carrying sarcoma tumors with pazopanib and valproate resulted in a greater than additive reduction in tumor volume compared with either drug individually. As both pazopanib and HDACIs are FDA-approved agents, our data argue for further determination as to whether this drug combination is a useful sarcoma therapy in the clinic.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/drug effects ; Autophagy-Related Protein 5 ; Beclin-1 ; Cell Line, Tumor ; Drug Synergism ; Female ; Gene Knockdown Techniques ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice, Nude ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Receptors, Death Domain/metabolism ; Sarcoma/drug therapy ; Sarcoma/metabolism ; Sarcoma/pathology ; Signal Transduction/drug effects ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Valproic Acid/therapeutic use
Chemical Substances	ATG5 protein, human ; Antineoplastic Agents ; Apoptosis Regulatory Proteins ; Autophagy-Related Protein 5 ; BECN1 protein, human ; Beclin-1 ; Histone Deacetylase Inhibitors ; Membrane Proteins ; Microtubule-Associated Proteins ; Pyrimidines ; Receptors, Death Domain ; Sulfonamides ; Valproic Acid (614OI1Z5WI) ; pazopanib (7RN5DR86CK)
Language	English
Publishing date	2014-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.28163
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Zs.A 5887: Show issues

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Article ; Online: Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells.

Hamed, Hossein A / Yamaguchi, Yukihiro / Fisher, Paul B / Grant, Steven / Dent, Paul

Journal of cellular physiology

2013 Volume 228, Issue 10, Page(s) 1996–2005

Abstract: The present studies were designed to compare and contrast the abilities of TRAIL (death receptor agonist) and obatoclax (BCL-2 family inhibitor) to enhance sorafenib + HDAC inhibitor toxicity in GI tumor cells. Sorafenib and HDAC inhibitor treatment ... ...

Abstract	The present studies were designed to compare and contrast the abilities of TRAIL (death receptor agonist) and obatoclax (BCL-2 family inhibitor) to enhance sorafenib + HDAC inhibitor toxicity in GI tumor cells. Sorafenib and HDAC inhibitor treatment required expression of CD95 to kill GI tumor cells in vitro and in vivo. In cells lacking CD95 expression, TRAIL treatment, and to a lesser extent obatoclax, enhanced the lethal effects of sorafenib + HDAC inhibitor exposure. In hepatoma cells expressing CD95 a similar data pattern emerged with respect to the actions of TRAIL. Downstream of the death receptor the ability of TRAIL to enhance cell killing correlated with reduced AKT, ERK1/2, p70 S6K, and mTOR activity and enhanced cleavage of pro-caspase 3 and reduced expression of MCL-1 and BCL-XL. Over-expression of BCL-XL or MCL-1 or expression of dominant negative pro-caspase 9 protected cells from drug toxicity. Expression of activated AKT, p70 S6K, mTOR, and to a lesser extent MEK1EE also protected cells that correlated with maintained c-FLIP-s expression, reduced BIM expression, and increased BAD phosphorylation. In vivo sorafenib + HDAC inhibitor toxicity against tumors was increased in a greater than additive fashion by TRAIL. Collectively, our data argue that TRAIL, rather than obatoclax, is the most efficacious agent at promoting sorafenib + HDAC inhibitor lethality.
MeSH term(s)	Animals ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Drug Synergism ; Female ; Hep G2 Cells ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Mice ; Mice, Nude ; Niacinamide/analogs & derivatives ; Niacinamide/pharmacology ; Phenylurea Compounds/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sorafenib ; TNF-Related Apoptosis-Inducing Ligand/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Xenograft Model Antitumor Assays ; bcl-2-Associated X Protein/metabolism ; bcl-Associated Death Protein/metabolism ; fas Receptor/metabolism
Chemical Substances	BAD protein, human ; CASP8 and FADD-Like Apoptosis Regulating Protein ; CFLAR protein, human ; Histone Deacetylase Inhibitors ; Phenylurea Compounds ; Proto-Oncogene Proteins c-bcl-2 ; TNF-Related Apoptosis-Inducing Ligand ; bcl-2-Associated X Protein ; bcl-Associated Death Protein ; fas Receptor ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; Caspase 3 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2013-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.24362
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Article ; Online: The role of cell signalling in the crosstalk between autophagy and apoptosis.

Booth, Laurence A / Tavallai, Seyedmehrad / Hamed, Hossein A / Cruickshanks, Nichola / Dent, Paul

Cellular signalling

2013 Volume 26, Issue 3, Page(s) 549–555

Abstract: Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be identified has taken centre stage as the principal mechanism of programmed cell death ( ... ...

Abstract	Not surprisingly, the death of a cell is a complex and well controlled process. For several decades, apoptosis, the first genetically programmed death process to be identified has taken centre stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Apoptosis has been extensively studied and its contribution to the pathogenesis of disease well documented. However, apoptosis does not function alone in determining the fate of a cell. More recently, autophagy, a process in which de novo formed membrane enclosed vesicles engulf and consume cellular components, has been shown to engage in complex interplay with apoptosis. As a result, cell death has been subdivided into the categories apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). The boundary between Type I and II cell death is not completely clear and as we will discuss in this review and perhaps a discrete difference does not exist, due to intrinsic factors among different cell types and crosstalk among organelles within each cell type. Apoptosis may begin with autophagy and autophagy can often end with apoptosis, inhibition or a blockade of caspase activity may lead a cell to default into Type II cell death from Type I.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Apoptosis/genetics ; Apoptosis/physiology ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/genetics ; Autophagy/physiology ; Beclin-1 ; Caspases/metabolism ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mitochondrial Membranes/metabolism ; Necrosis/genetics ; Sequestosome-1 Protein ; Signal Transduction
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Membrane Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2013-12-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2013.11.028
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Zs.A 2579: Show issues

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Article ; Online: Obatoclax and lapatinib interact to induce toxic autophagy through NOXA.

Tang, Yong / Hamed, Hossein A / Cruickshanks, Nichola / Fisher, Paul B / Grant, Steven / Dent, Paul

Molecular pharmacology

2012 Volume 81, Issue 4, Page(s) 527–540

Abstract: Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by ... ...

Abstract	Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax-initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Autophagy/drug effects ; Cell Death ; Cell Line, Tumor ; Genes, erbB-2 ; Humans ; Lapatinib ; Proto-Oncogene Proteins c-bcl-2/physiology ; Pyrroles/pharmacology ; Quinazolines/pharmacology
Chemical Substances	Antineoplastic Agents ; PMAIP1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles ; Quinazolines ; Lapatinib (0VUA21238F) ; obatoclax (QN4128B52A)
Language	English
Publishing date	2012-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.111.076851
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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 mammary tumors.

Tang, Yong / Hamed, Hossein A / Poklepovic, Andrew / Dai, Yun / Grant, Steven / Dent, Paul

Molecular pharmacology

2012 Volume 82, Issue 2, Page(s) 322–332

Abstract: The present studies sought to define whether checkpoint kinase 1 (CHK1) inhibitors and poly(ADP-ribose) polymerase 1 (PARP1) inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill estrogen ... ...

Abstract	The present studies sought to define whether checkpoint kinase 1 (CHK1) inhibitors and poly(ADP-ribose) polymerase 1 (PARP1) inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill estrogen receptor (ER)+, ER+ fulvestrant-resistant, HER2+, or triple-negative mammary carcinoma cells in a manner that was not apparently affected by phosphatase and tensin homolog deleted on chromosome 10 functional status. Expression of dominant-negative CHK1 enhanced and overexpression of wild-type CHK1 suppressed the toxicity of PARP1 inhibitors in a dose-dependent fashion. Knockdown of PARP1 enhanced the lethality of CHK1 inhibitors in a dose-dependent fashion. PARP1 and CHK1 inhibitors interacted in vivo both to suppress the growth of large established tumors and to suppress the growth of smaller developing tumors; the combination enhanced animal survival. PARP1 and CHK1 inhibitors profoundly radiosensitized cells in vitro and in vivo. In conclusion, our data demonstrate that the combination of PARP1 and CHK1 inhibitors has antitumor activity in vivo against multiple mammary tumor types and that translation of this approach could prove to be a useful anticancer therapeutic approach.
MeSH term(s)	Animals ; Benzimidazoles/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Death/drug effects ; Cell Death/physiology ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Humans ; Mice ; Mice, Nude ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/physiology ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinases/genetics ; Protein Kinases/metabolism ; Protein Kinases/physiology ; Xenograft Model Antitumor Assays/methods
Chemical Substances	Benzimidazoles ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; veliparib (01O4K0631N) ; 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) ; Chek1 protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2012-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.112.078907
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 525: Show issues

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Article ; Online: Nexavar/Stivarga and viagra interact to kill tumor cells.

Tavallai, Mehrad / Hamed, Hossein A / Roberts, Jane L / Cruickshanks, Nichola / Chuckalovcak, John / Poklepovic, Andrew / Booth, Laurence / Dent, Paul

Journal of cellular physiology

2014 Volume 230, Issue 9, Page(s) 2281–2298

Abstract: We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared ...

Abstract	We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by 'rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients.
MeSH term(s)	Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 5/biosynthesis ; Cyclic Nucleotide Phosphodiesterases, Type 5/genetics ; Drug Synergism ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Knockdown Techniques ; Hep G2 Cells ; Humans ; Neoplasm Proteins/biosynthesis ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Niacinamide/administration & dosage ; Niacinamide/analogs & derivatives ; Phenylurea Compounds/administration & dosage ; Phosphodiesterase 5 Inhibitors/administration & dosage ; Piperazines/administration & dosage ; Purines/administration & dosage ; Signal Transduction/drug effects ; Sildenafil Citrate ; Sorafenib ; Sulfonamides/administration & dosage ; Xenograft Model Antitumor Assays
Chemical Substances	Neoplasm Proteins ; Phenylurea Compounds ; Phosphodiesterase 5 Inhibitors ; Piperazines ; Purines ; Sulfonamides ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; Sildenafil Citrate (BW9B0ZE037) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35)
Language	English
Publishing date	2014-11-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.24961
Database	MEDical Literature Analysis and Retrieval System OnLINE

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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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sorafenib/regorafenib and phosphatidyl inositol 3 kinase/thymoma viral proto-oncogene inhibition interact to kill tumor cells.

Sajithlal, Gangadharan B / Hamed, Hossein A / Cruickshanks, Nichola / Booth, Laurence / Tavallai, Seyedmehrad / Syed, Jahangir / Grant, Steven / Poklepovic, Andrew / Dent, Paul

Molecular pharmacology

2013 Volume 84, Issue 4, Page(s) 562–571

Abstract: The present studies were undertaken to determine whether the multikinase inhibitors sorafenib/regorafenib cooperated with clinically relevant , phosphatidyl inositol 3 kinase (PI3K)-thymoma viral proto-oncogene (AKT) inhibitors to kill tumor cells. In ... ...

Abstract	The present studies were undertaken to determine whether the multikinase inhibitors sorafenib/regorafenib cooperated with clinically relevant , phosphatidyl inositol 3 kinase (PI3K)-thymoma viral proto-oncogene (AKT) inhibitors to kill tumor cells. In liver, colorectal, lung, breast, kidney, and brain cancer cells, at clinically achievable doses, sorafenib/regorafenib and the PI3K inhibitor acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester (PX-866) cooperated in a greater than additive fashion to kill tumor cells. Cells lacking phosphatase and tensin homolog were as sensitive to the drug combination as cells expressing the protein. Similar data were obtained using the AKT inhibitors perifosine and 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-1,2,4-triazolo[3,4-f] [1,6]naphthyridin-3(2H)-one hydrochloride (MK2206). PX-866 treatment abolished AKT/glycogen synthase kinase 3 (GSK3) phosphorylation, and cell killing correlated with reduced activity of AKT and mammalian target of rapamycin (mTOR). Expression of activated AKT and to a lesser extent activated mTOR reduced drug combination lethality. Expression of B-cell lymphoma-extra large or dominant negative caspase 9, but not cellular FLICE (FADD-like IL-1b-converting enzyme)-inhibitory protein short, protected cells from the drug combination. Treatment of cells with PX-866 increased protein levels of p62, lysosome-associated membrane protein 2 (LAMP2), and microtubule-associated protein light chain (LC) 3 and LC3II that correlated with a large increase in LC3-green fluorescent protein (GFP) vesicle numbers. Exposure of PX-866 treated cells to sorafenib reduced p62 and LAMP2 levels, decreased the ratio of LC3 to LC3II, and reduced LC3-GFP vesicle levels. Knockdown of Beclin1 or autophagy-related 5 suppressed drug toxicity by ∼40%. In vivo, sorafenib and PX-866 or regorafenib and MK2206 cooperated to suppress the growth of established HuH7 and HCT116 tumors, respectively. Collectively our data demonstrate that the combination of sorafenib family kinase inhibitors with inhibitors of the PI3K/AKT pathway kills tumor cells in vitro and in vivo.
MeSH term(s)	Animals ; Cell Communication/drug effects ; Cell Communication/physiology ; Cell Death/drug effects ; Cell Death/physiology ; Cell Line, Tumor ; Drug Synergism ; Female ; Gonanes/administration & dosage ; Hep G2 Cells ; Humans ; Mice ; Niacinamide/administration & dosage ; Niacinamide/analogs & derivatives ; Phenylurea Compounds/administration & dosage ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines/administration & dosage ; Sorafenib ; Thymoma/drug therapy ; Thymoma/metabolism ; Thymoma/pathology ; Thymus Neoplasms/drug therapy ; Thymus Neoplasms/metabolism ; Thymus Neoplasms/pathology ; Xenograft Model Antitumor Assays
Chemical Substances	Gonanes ; PX-866 ; Phenylurea Compounds ; Phosphoinositide-3 Kinase Inhibitors ; Pyridines ; regorafenib (24T2A1DOYB) ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2013-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.113.088005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy.

Cruickshanks, Nichola / Hamed, Hossein A / Booth, Laurence / Tavallai, Seyedmehrad / Syed, Jahangir / Sajithlal, Gangadharan B / Grant, Steven / Poklepovic, Andrew / Dent, Paul

Cancer biology & therapy

2013 Volume 14, Issue 10, Page(s) 982–996

Abstract: The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, ... ...

Abstract	The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells. Pre-treatment of anoikis-resistant cells with histone deacetylase inhibitors (HDACIs) for 24 h increased the levels of toxic BH3 domain proteins, reduced MCL-1 levels, and restored/re-sensitized the cell death response of AR tumor cells to multiple toxic therapies. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored the chemo-sensitivity of the tumors and prolonged animal survival. These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.
MeSH term(s)	Animals ; Anoikis ; Antineoplastic Agents, Hormonal/pharmacology ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Survival ; Drug Resistance, Neoplasm ; Epigenesis, Genetic/drug effects ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Female ; Gene Expression/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockdown Techniques ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Lapatinib ; Mice ; Mice, Nude ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; RNA, Small Interfering/genetics ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/metabolism ; Valproic Acid/pharmacology ; Xenograft Model Antitumor Assays ; bcl-2 Homologous Antagonist-Killer Protein/genetics ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/genetics ; bcl-X Protein/metabolism
Chemical Substances	Antineoplastic Agents, Hormonal ; Apoptosis Regulatory Proteins ; BAK1 protein, human ; BAX protein, human ; BBC3 protein, human ; BCL2L1 protein, human ; Histone Deacetylase Inhibitors ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; PMAIP1 protein, human ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles ; Quinazolines ; RNA, Small Interfering ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; bcl-X Protein ; Lapatinib (0VUA21238F) ; Valproic Acid (614OI1Z5WI) ; EGFR protein, human (EC 2.7.10.1) ; ERBB2 protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; obatoclax (QN4128B52A)
Language	English
Publishing date	2013-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2146305-0
ISSN	1555-8576 ; 1538-4047
ISSN (online)	1555-8576
ISSN	1538-4047
DOI	10.4161/cbt.26234
Database	MEDical Literature Analysis and Retrieval System OnLINE

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