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  1. AU="Ningaraj, Nagendra S"
  2. AU="Deegan, Patrick"
  3. AU="Jo, Doo Sin"
  4. AU="Adgey, A J"
  5. AU=Liu Hejun
  6. AU="Ferreira, Filipa C"
  7. AU="Losurdo, G"
  8. AU="Dorjsuren, Bilguujin"
  9. AU="Kilgore, Henry R"
  10. AU="Magee, Toni"
  11. AU="Jiang Gui"

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  1. Artikel: Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors.

    Khaitan, Divya / Ningaraj, Nagendra S

    Frontiers in pharmacology

    2013  Band 4, Seite(n) 62

    Abstract: Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a ... ...

    Abstract Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents' delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome.
    Sprache Englisch
    Erscheinungsdatum 2013-05-29
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2013.00062
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Drug delivery to brain tumours: challenges and progress.

    Ningaraj, Nagendra S

    Expert opinion on drug delivery

    2006  Band 3, Heft 4, Seite(n) 499–509

    Abstract: Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor ... ...

    Abstract Nearly 12.5 million new cancer cases are diagnosed worldwide each year. Although new treatments have been developed, most new anticancer drugs that are effective outside the brain have failed in clinical trials against brain tumours, in part due to poor penetration across the blood-brain barrier and the blood-brain tumour barrier. This review will discuss the challenges of drug delivery across the blood-brain barrier/blood-brain tumour barrier to cancer cells, as well as progress made so far. This will include a biochemical modulation strategy that transiently opens the barrier to increase anticancer drug delivery selectively to brain tumours. It will also briefly discuss a quantitative non-invasive method to measure permeability changes and tumour response to treatment in the human brain.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/therapeutic use ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Drug Delivery Systems ; Humans
    Chemische Substanzen Antineoplastic Agents
    Sprache Englisch
    Erscheinungsdatum 2006-07
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2167286-6
    ISSN 1744-7593 ; 1742-5247
    ISSN (online) 1744-7593
    ISSN 1742-5247
    DOI 10.1517/17425247.3.4.499
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Modulation of brain tumor capillaries for enhanced drug delivery selectively to brain tumor.

    Black, Keith L / Ningaraj, Nagendra S

    Cancer control : journal of the Moffitt Cancer Center

    2004  Band 11, Heft 3, Seite(n) 165–173

    Abstract: Background: The blood-brain tumor barrier (BTB) significantly impedes delivery of most hydrophilic molecules to brain tumors. Several promising strategies, however, have been developed to overcome this problem.: Methods: We discuss several drug ... ...

    Abstract Background: The blood-brain tumor barrier (BTB) significantly impedes delivery of most hydrophilic molecules to brain tumors. Several promising strategies, however, have been developed to overcome this problem.
    Methods: We discuss several drug delivery methods to brain tumor, including intracerebroventricular, convection enhanced delivery, BBB/BTB disruption, and BTB permeability modulation, which was developed in our laboratory.
    Results: Using immunolocalization, immunoblotting, and potentiometric studies, we found that brain tumor capillary endothelial cells overexpress certain unique protein markers that are absent or barely detectable in normal capillary endothelial cells. We biochemically modulated these markers to sustain and enhance drug delivery, including molecules of varying sizes, selectively to tumors in rat syngeneic and xenograft brain tumor models. We also demonstrated that the cellular mechanism for vasomodulator-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles that transport therapeutic molecules across the BTB.
    Conclusions: Other methods to deliver drugs across the BTB are effective but have severe drawbacks. Our strategy targets BTB-specific proteins to increase antineoplastic drug delivery selectively to brain tumors with few or no side effects, thus increasing the possibility of improving brain tumor treatment.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/administration & dosage ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Bradykinin/administration & dosage ; Brain Neoplasms/blood supply ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Capillary Permeability/drug effects ; Cyclic GMP-Dependent Protein Kinases/administration & dosage ; Drug Delivery Systems/instrumentation ; Drug Delivery Systems/methods ; Endothelium-Dependent Relaxing Factors/administration & dosage ; Humans ; Infusions, Parenteral/methods ; Leukotriene A4/administration & dosage ; Nitric Oxide/administration & dosage ; Potassium Channels/metabolism ; Rats ; Vasodilator Agents/administration & dosage
    Chemische Substanzen Antineoplastic Agents ; Endothelium-Dependent Relaxing Factors ; Leukotriene A4 ; Potassium Channels ; Vasodilator Agents ; Nitric Oxide (31C4KY9ESH) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Bradykinin (S8TIM42R2W)
    Sprache Englisch
    Erscheinungsdatum 2004-05
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1328503-8
    ISSN 1526-2359 ; 1073-2748
    ISSN (online) 1526-2359
    ISSN 1073-2748
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Adenosine 5'-triphosphate-sensitive potassium channel-mediated blood-brain tumor barrier permeability increase in a rat brain tumor model.

    Ningaraj, Nagendra S / Rao, Mamatha K / Black, Keith L

    Cancer research

    2003  Band 63, Heft 24, Seite(n) 8899–8911

    Abstract: Brain tumor microvessels/capillaries limit drug delivery to tumors by forming a blood-brain tumor barrier (BTB). The BTB overexpresses ATP-sensitive potassium (K(ATP)) channels that are barely detectable in normal brain capillaries, and which were ... ...

    Abstract Brain tumor microvessels/capillaries limit drug delivery to tumors by forming a blood-brain tumor barrier (BTB). The BTB overexpresses ATP-sensitive potassium (K(ATP)) channels that are barely detectable in normal brain capillaries, and which were targeted for BTB permeability modulation. In a rat brain tumor model, we infused minoxidil sulfate (MS), a selective K(ATP) channel activator, to obtain sustained, enhanced, and selective drug delivery, including various sized molecules, across the BTB to brain tumors. Glibenclamide, a selective K(ATP) channel inhibitor, significantly attenuated the MS-induced BTB permeability increase. Immunocytochemistry and glibenclamide binding studies showed increased K(ATP) channel density distribution on tumor cells and tumor capillary endothelium, which was confirmed by K(ATP) channel potentiometric assay in tumor cells and brain endothelial cells cocultured with brain tumor cells. MS infusion in rats with brain tumors significantly increased transport vesicle density in tumor capillary endothelial and tumor cells. MS facilitated increased delivery of macromolecules, including Her-2 antibody, adenoviral-green fluorescent protein, and carboplatin, to brain tumors, with carboplatin significantly increasing survival in brain tumor-bearing rats. K(ATP) channel-mediated BTB permeability increase was also demonstrated in a human, brain tumor xenograft model. We conclude that K(ATP) channels are a potential target for biochemical modulation of BTB permeability to increase antineoplastic drug delivery selectively to brain tumors.
    Mesh-Begriff(e) Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/pharmacokinetics ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/blood supply ; Brain Neoplasms/metabolism ; Cell Membrane Permeability/physiology ; Drug Synergism ; Endothelium, Vascular/metabolism ; Female ; Genetic Vectors/pharmacokinetics ; Glioma/blood supply ; Glioma/metabolism ; Glyburide/pharmacology ; Green Fluorescent Proteins ; Humans ; Luminescent Proteins/biosynthesis ; Luminescent Proteins/genetics ; Minoxidil/analogs & derivatives ; Minoxidil/pharmacology ; Molecular Sequence Data ; Potassium Channel Blockers/pharmacokinetics ; Potassium Channel Blockers/pharmacology ; Potassium Channels/agonists ; Potassium Channels/metabolism ; Rats ; Rats, Wistar ; Receptor, ErbB-2/immunology ; Xenograft Model Antitumor Assays
    Chemische Substanzen Antibodies, Monoclonal ; Luminescent Proteins ; Potassium Channel Blockers ; Potassium Channels ; Green Fluorescent Proteins (147336-22-9) ; minoxidil sulfate ester (2H6K6Y231J) ; Minoxidil (5965120SH1) ; Adenosine Triphosphate (8L70Q75FXE) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Glyburide (SX6K58TVWC)
    Sprache Englisch
    Erscheinungsdatum 2003-12-15
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Calcium-dependent potassium channels as a target protein for modulation of the blood-brain tumor barrier.

    Ningaraj, Nagendra S / Rao, Mamatha / Black, Keith L

    Drug news & perspectives

    2003  Band 16, Heft 5, Seite(n) 291–298

    Abstract: Even though the blood-brain tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), the BTB still significantly restricts the delivery of anticancer drugs to brain tumors. Brain tumor capillaries that form the BTB, however, express ... ...

    Abstract Even though the blood-brain tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), the BTB still significantly restricts the delivery of anticancer drugs to brain tumors. Brain tumor capillaries that form the BTB, however, express certain unique protein markers that are absent or barely detectable in normal brain capillaries. We were able to biochemically modulate one such protein marker, the calcium-dependent potassium (K(Ca)) channel, by using a specific K(Ca) channel agonist, NS-1619, to obtain sustained enhancement of selective drug delivery, including molecules of varying sizes, to tumors in rat syngeneic and xenograft brain tumor models. Immunolocalization and potentiometric studies showed increased K(Ca) channel distribution on tumor cells compared with normal cells, suggesting that tumor cell-specific signals might induce overexpression of K(Ca) channels in capillary endothelial cells, leading to increased BTB permeability. We also demonstrated that the cellular mechanism for K(Ca) channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport therapeutic molecules across the BTB. This concept was investigated by using NS-1619 to facilitate increased delivery of carboplatin to brain tumor leading to enhanced survival in rats with brain tumors. Additionally, we showed that K(Ca) channel modulation resulted in enhanced permeability to macromolecules, including Her-2 monoclonal antibody and green fluorescent protein-adenoviral vectors, in a human, primary brain-tumor xenograft model. Therefore, K(Ca) channels are a potential, promising target for biochemical modulation of BTB permeability to increase antineoplastic drug delivery selectively to brain tumors.
    Mesh-Begriff(e) Animals ; Benzimidazoles/administration & dosage ; Benzimidazoles/pharmacokinetics ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/physiology ; Brain/blood supply ; Brain/drug effects ; Brain Neoplasms/blood supply ; Brain Neoplasms/drug therapy ; Brain Neoplasms/pathology ; Capillary Permeability/drug effects ; Carboplatin/administration & dosage ; Carboplatin/pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Humans ; Neoplasm Metastasis/drug therapy ; Potassium Channels, Calcium-Activated/administration & dosage ; Potassium Channels, Calcium-Activated/physiology ; Rats ; Rats, Wistar
    Chemische Substanzen Benzimidazoles ; Drug Carriers ; Potassium Channels, Calcium-Activated ; NS 1619 (153587-01-0) ; Carboplatin (BG3F62OND5)
    Sprache Englisch
    Erscheinungsdatum 2003-08-14
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 885125-6
    ISSN 2013-0139 ; 0214-0934
    ISSN (online) 2013-0139
    ISSN 0214-0934
    DOI 10.1358/dnp.2003.16.5.878815
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model.

    Ningaraj, Nagendra S / Sankpal, Umesh T / Khaitan, Divya / Meister, Edward A / Vats, Tribhawan S

    Cancer biology & therapy

    2009  Band 8, Heft 20, Seite(n) 1924–1933

    Abstract: Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab ( ... ...

    Abstract Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.
    Mesh-Begriff(e) Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis/drug effects ; Benzimidazoles/administration & dosage ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Dacarbazine/administration & dosage ; Dacarbazine/analogs & derivatives ; Dacarbazine/pharmacokinetics ; Drug Delivery Systems ; Female ; Flow Cytometry ; Glioma/drug therapy ; Glioma/metabolism ; Glioma/pathology ; Humans ; Immunoblotting ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/agonists ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism ; Mice ; Mice, Nude ; Rats ; Rats, Nude ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Analysis ; Temozolomide ; Trastuzumab ; Xenograft Model Antitumor Assays/methods
    Chemische Substanzen Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Benzimidazoles ; KCNMA1 protein, human ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits ; NS 1619 (153587-01-0) ; Dacarbazine (7GR28W0FJI) ; Trastuzumab (P188ANX8CK) ; Temozolomide (YF1K15M17Y)
    Sprache Englisch
    Erscheinungsdatum 2009-10-12
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146305-0
    ISSN 1555-8576 ; 1538-4047
    ISSN (online) 1555-8576
    ISSN 1538-4047
    DOI 10.4161/cbt.8.20.9490
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Activation of KATP channels increases anticancer drug delivery to brain tumors and survival.

    Ningaraj, Nagendra S / Sankpal, Umesh T / Khaitan, Divya / Meister, Edward A / Vats, Trib

    European journal of pharmacology

    2009  Band 602, Heft 2-3, Seite(n) 188–193

    Abstract: Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which ... ...

    Abstract Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2/neu over expressing gliomas may work well when combined with temozolomide. Nonetheless, both drugs do not cross the BTB to significantly impact patient survival. Beforehand we showed that potassium channel agonists when intracarotidly administered increased carboplatin and Her-2 antibody delivery in animal glioma models by triggering formation of brain vascular endothelial transcytotic vesicles. In this study, we investigated whether, intravenously administered, ATP-sensitive potassium channel (K(ATP)) activator (minoxidil sulfate; MS) increases temozolomide and Herceptin delivery to brain tumors to induce anti-tumor activity and increase survival in nude mice with Glioblastoma multiforme (GBM) cells. The results clearly demonstrate that when given intravenously temozolomide crosses BTB at a relatively low amount while Herceptin failed to cross the BTB. However, MS co-infusion with [(14)C]-temozolomide or fluorescently labeled-Herceptin resulted in improved and selective drug delivery to brain tumor. We also showed that combination treatment with temozolomide and Herceptin has enhanced anti-tumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with GBM when co-infused with MS. Therefore, brain tumor patients may be benefited when anti-neoplastic agent delivery is increased selectively to the brain tumors using KATP channel agonists.
    Mesh-Begriff(e) Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Carbon Radioisotopes/chemistry ; Cell Line, Tumor ; Dacarbazine/administration & dosage ; Dacarbazine/analogs & derivatives ; Dacarbazine/chemistry ; Dacarbazine/metabolism ; Dacarbazine/pharmacology ; Drug Delivery Systems/methods ; Gene Expression Regulation, Neoplastic ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Humans ; KATP Channels/agonists ; KATP Channels/genetics ; KATP Channels/metabolism ; Mice ; Minoxidil/analogs & derivatives ; Minoxidil/pharmacology ; Survival Rate ; Transplantation, Heterologous ; Trastuzumab
    Chemische Substanzen Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Carbon Radioisotopes ; KATP Channels ; minoxidil sulfate ester (2H6K6Y231J) ; Minoxidil (5965120SH1) ; Dacarbazine (7GR28W0FJI) ; Trastuzumab (P188ANX8CK) ; temozolomide (YF1K15M17Y)
    Sprache Englisch
    Erscheinungsdatum 2009-01-14
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2008.10.056
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Role of KCNMA1 gene in breast cancer invasion and metastasis to brain

    Couraud Pierre-Olivier / Romero Ignacio A / Meister Edward A / Weksler Babette / Sankpal Umesh T / Khaitan Divya / Ningaraj Nagendra S

    BMC Cancer, Vol 9, Iss 1, p

    2009  Band 258

    Abstract: Abstract Background The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence ... ...

    Abstract Abstract Background The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BK Ca ) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BK Ca channels in breast cancer metastasis and invasion. Methods We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BK Ca channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BK Ca channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX). Results The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BK Ca channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1 . Conclusion Determining the relative abundance of BK Ca channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.
    Schlagwörter Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Thema/Rubrik (Code) 616 ; 610
    Sprache Englisch
    Erscheinungsdatum 2009-07-01T00:00:00Z
    Verlag BioMed Central
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  9. Artikel: Disulfiram Augments Oxidative Stress in Rat Brain following Bilateral Carotid Artery Occlusion

    Ningaraj, Nagendra S. / Rao, Mamatha K.

    Journal of Biomedical Science

    1998  Band 5, Heft 3, Seite(n) 226–230

    Abstract: We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram ...

    Körperschaft Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India
    Abstract We examined the brain oxidative stress which accompanies 30 min of bilateral carotid artery ligation (BCAL) in terms of changes in brain levels of glutathione; reduced (GSH) and oxidized (GSSG) forms and the exacerbation of oxidative stress by disulfiram (DSF). These results indicate that BCAL alone decreases GSH content and limits glutathione reductase (GR) activity, and these changes were enhanced by DSF pretreatment. Similar observations were recorded with DSF alone. GR activity (74.3 ± 4.0 µmol min–1 mg–1 tissue; p < 0.001) and GSH content (1.23 ± 0.06 µmol min–1 g–1 tissue; p < 0.001) was attenuated in rats subjected to synergistic effect of BCAL and DSF with a concomitant increase of GSSG (0.006 ± 0.006 µmol min–1 g–1 tissue; p < 0.001). Recovery of GSH/GSSG level and GR activity during reperfusion following 30 min BCAL was considerably delayed (96 h) in the BCAL and DSF group as compared to the recovery time of 24 h in the group subjected to BCAL-reperfusion alone. Perturbation of GSH/GSSG homeostasis as a result of BCAL was augmented by DSF. These findings clearly demonstrate central nervous system oxidative stress due to a BCAL-DSF synergistic effect. Based on the results obtained with this model, we conclude that DSF increases brain oxidative stress and this may be detrimental to alcoholics who might drink and develop an acetaldehyde-induced hypotension while taking DSF.
    Schlagwörter Disulfiram ; Ischemia ; Reperfusion ; GSH ; Oxidative stress
    Sprache Englisch
    Erscheinungsdatum 1998-07-02
    Verlag S. Karger AG
    Erscheinungsort Basel, Switzerland
    Dokumenttyp Artikel
    Anmerkung Original Paper
    ZDB-ID 1193378-1
    ISSN 1423-0127 ; 1021-7770
    ISSN (online) 1423-0127
    ISSN 1021-7770
    DOI 10.1159/000025335
    Datenquelle Karger Verlag

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  10. Artikel ; Online: Role of KCNMA1 gene in breast cancer invasion and metastasis to brain.

    Khaitan, Divya / Sankpal, Umesh T / Weksler, Babette / Meister, Edward A / Romero, Ignacio A / Couraud, Pierre-Olivier / Ningaraj, Nagendra S

    BMC cancer

    2009  Band 9, Seite(n) 258

    Abstract: Background: The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of ... ...

    Abstract Background: The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming alpha-subunit of BKCa channels in breast cancer metastasis and invasion.
    Methods: We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX).
    Results: The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1.
    Conclusion: Determining the relative abundance of BKCa channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.
    Mesh-Begriff(e) Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/secondary ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Membrane/metabolism ; Cell Movement ; Exons ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/physiology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Peptides/pharmacology ; Prognosis ; RNA, Small Interfering/metabolism
    Chemische Substanzen KCNMA1 protein, human ; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits ; Peptides ; RNA, Small Interfering ; iberiotoxin (773HER9B6T)
    Sprache Englisch
    Erscheinungsdatum 2009-07-29
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-2407
    ISSN (online) 1471-2407
    DOI 10.1186/1471-2407-9-258
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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