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1.
Mol Cancer Ther ; 15(9): 2018-29, 2016 09.
Article in English | MEDLINE | ID: mdl-27325686

ABSTRACT

Glioblastoma multiforme is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with glioblastoma multiforme beyond 14 to 15 months, in part because the blood-brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as glioblastoma multiforme treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests glioblastoma multiforme cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood-brain barrier. Further investigation in a syngeneic orthotopic mouse model of glioblastoma multiforme shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. Mol Cancer Ther; 15(9); 2018-29. ©2016 AACR.


Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Microtubules/metabolism , Tubulin Modulators/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Caspase 3/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Glioblastoma/drug therapy , Glioblastoma/pathology , Humans , Mice , Nanoparticles , Pilot Projects , Solubility , Tubulin Modulators/administration & dosage , Tubulin Modulators/pharmacokinetics , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
2.
Neurobiol Dis ; 71: 140-50, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25134728

ABSTRACT

Huntington's disease (HD) is caused by an expanded polyglutamine repeat in huntingtin protein that disrupts synaptic function in specific neuronal populations and results in characteristic motor, cognitive and affective deficits. Histopathological hallmarks observed in both HD patients and genetic mouse models include the reduced expression of synaptic proteins, reduced medium spiny neuron (MSN) dendritic spine density and decreased frequency of spontaneous excitatory post-synaptic currents (sEPSCs). Early down-regulation of cannabinoid CB1 receptor expression on MSN (CB1(MSN)) is thought to participate in HD pathogenesis. Here we present a cell-specific genetic rescue of CB1(MSN) in R6/2 mice and report that treatment prevents the reduction of excitatory synaptic markers in the striatum (synaptophysin, vGLUT1 and vGLUT2), of dendritic spine density on MSNs and of MSN sEPSCs, but does not prevent motor impairment. We conclude that loss of excitatory striatal synapses in HD mice is controlled by CB1(MSN) and can be uncoupled from the motor phenotype.


Subject(s)
Corpus Striatum/pathology , Huntington Disease/therapy , Motor Activity/genetics , Neurons/metabolism , Receptor, Cannabinoid, CB1/metabolism , Synapses/physiology , Action Potentials/genetics , Animals , Excitatory Postsynaptic Potentials/genetics , Female , Gene Expression Regulation/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/physiopathology , Male , Mice , Mice, Transgenic , Muscle Strength/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/pathology , Neurons/ultrastructure , Nuclear Proteins/genetics , Receptor, Cannabinoid, CB1/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Silver Staining , Time Factors
3.
Neuron ; 83(2): 361-371, 2014 Jul 16.
Article in English | MEDLINE | ID: mdl-25033180

ABSTRACT

The serine hydrolase α/ß-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.


Subject(s)
Anticonvulsants/therapeutic use , Brain/drug effects , Carbamates/therapeutic use , Monoacylglycerol Lipases/antagonists & inhibitors , Seizures/drug therapy , Animals , Anticonvulsants/pharmacology , Behavior, Animal/drug effects , Brain/physiopathology , Carbamates/pharmacology , Male , Mice , Mice, Knockout , Pentylenetetrazole , Receptors, Cannabinoid/genetics , Seizures/chemically induced , Seizures/physiopathology
4.
Eur J Neurosci ; 37(3): 429-40, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23167744

ABSTRACT

Cannabinoid receptor 1 (CB(1) receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB(1) expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB(1) signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB(1) downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi-quantitative immunohistochemistry, we confirmed previous studies showing that CB(1) expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB(1) is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB(1) downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, Hdh(Q150/Q150) mice and the caudate nucleus of patients with HD. In R6/2 mice, CB(1) downregulation in NPY/nNOS-expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro-survival signaling molecule cAMP response element-binding protein in NPY/nNOS-expressing interneurons. Loss of CB(1) signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.


Subject(s)
Basal Ganglia/metabolism , Down-Regulation , Huntington Disease/metabolism , Interneurons/metabolism , Neuropeptide Y/metabolism , Receptor, Cannabinoid, CB1/metabolism , Adult , Aged , Animals , Basal Ganglia/cytology , Calbindin 2 , Cannabinoid Receptor Agonists/pharmacology , Case-Control Studies , Cyclic AMP/metabolism , Disease Models, Animal , Female , Gene Expression , Humans , Huntingtin Protein , Interneurons/classification , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Nerve Tissue Proteins/genetics , Neuropeptide Y/genetics , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nuclear Proteins/genetics , Parvalbumins/genetics , Parvalbumins/metabolism , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/genetics , S100 Calcium Binding Protein G/genetics , S100 Calcium Binding Protein G/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism
5.
Mol Cell ; 48(4): 547-59, 2012 Nov 30.
Article in English | MEDLINE | ID: mdl-23063527

ABSTRACT

The mitogenic and second-messenger signals that promote cell proliferation often proceed through multienzyme complexes. The kinase-anchoring protein Gravin integrates cAMP and calcium/phospholipid signals at the plasma membrane by sequestering protein kinases A and C with G protein-coupled receptors. In this report we define a role for Gravin as a temporal organizer of phosphorylation-dependent protein-protein interactions during mitosis. Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. Fluorescent live-cell imaging reveals that cells depleted of Gravin exhibit mitotic defects that include protracted prometaphase and misalignment of chromosomes. Moreover, a Gravin T766A phosphosite mutant that is unable to interact with Plk1 negatively impacts cell proliferation. In situ detection of phospho-T766 Gravin in biopsy sections of human glioblastomas suggests that this phosphorylation event might identify malignant neoplasms.


Subject(s)
A Kinase Anchor Proteins/metabolism , Cell Cycle Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , A Kinase Anchor Proteins/genetics , Animals , Cell Cycle Proteins/genetics , Cell Division , Cell Proliferation , Humans , Mice , Mitosis , Phosphorylation , Protein Binding , Tumor Cells, Cultured , Polo-Like Kinase 1
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