Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.6.4.4 (
kinesin
)
5,033
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic
kinesin
KIF11
, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
...
PMID:Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma. 3230 Jan 51
KIF11
is a homotetrameric
kinesin
that peaks in protein expression during mitosis. It is a known mitotic regulator, and it is well-described that
KIF11
is necessary for the formation and maintenance of the bipolar spindle. However, there has been a growing appreciation for non-mitotic roles for
KIF11
.
KIF11
has been shown to function in such processes as axon growth and microtubule polymerization. We previously demonstrated that there is an interphase pool of
KIF11
present in glioblastoma cancer stem cells that drives tumor cell invasion. Here, we identified a previously unknown association between
KIF11
and primary cilia. We confirmed that
KIF11
localized to the basal bodies of primary cilia in multiple cell types, including neoplastic and non-neoplastic cells. Further, we determined that
KIF11
has a role in regulating cilia dynamics. Upon the reduction of
KIF11
expression, the number of ciliated cells in asynchronously growing populations was significantly increased. We rescued this effect by the addition of exogenous
KIF11
. Lastly, we found that depleting
KIF11
resulted in an increase in cilium length and an attenuation in the kinetics of cilia disassembly. These findings establish a previously unknown link between
KIF11
and the dynamics of primary cilia and further support non-mitotic functions for this
kinesin
.
...
PMID:An interphase pool of KIF11 localizes at the basal bodies of primary cilia and a reduction in KIF11 expression alters cilia dynamics. 3281 79
Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple
MYCN
-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of
kinesin
spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene
KIF11
was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that
KIF11
is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of
MYCN
-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.
...
PMID:Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma. 3296 73
Reactive oxygen species, particularly hydrogen peroxide (H
2
O
2
), can induce proliferation inhibition and death of A549 cells via oxidative stress. Oxidative stress has effect on DNA methylation. Oxidative stress and DNA methylation feature a common denominator: The one carbon cycle. To explore the inhibitory mechanism of H
2
O
2
on the proliferation of lung cancer cells, the present study analysed the mRNA expression and methylation profiles in A549 cells treated with H
2
O
2
for 24 h, as adenocarcinoma is the most common pathological type of lung cancer. The DNA methylation profile was constructed using reduced representation bisulphite sequencing, which identified 29,755 differentially methylated sites (15,365 upregulated and 14,390 downregulated), and 1,575 differentially methylated regions located in the gene promoters were identified using the methylKit. Analysis of the assocaition between gene expression and methylation levels revealed that several genes were downregulated and hypermethylated, including cyclin-dependent kinase inhibitor 3, denticleless E3 ubiquitin protein ligase homolog, centromere protein (CENP)F,
kinesin
family member (KIF)20A, CENPA,
KIF11
, PCNA clamp-associated factor and GINS complex subunit 2, which may be involved in the inhibitory process of H
2
O
2
on the proliferation of A549 cells.
...
PMID:mRNA expression and DNA methylation analysis of the inhibitory mechanism of H
2
O
2
on the proliferation of A549 cells. 3301 66
<< Previous
1
2
3
4
5
6
7
