Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca(2+) and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na(+), which compromised Na(+)-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. ©2017 AACR.

• MeSH
• aminokyseliny metabolismus   MeSH
• biologický transport MeSH
• blokátory kalciových kanálů farmakologie   MeSH
• buněčná smrt MeSH
• dihydropyridiny farmakologie   MeSH
• draslíkové kanály aktivované vápníkem antagonisté a inhibitory   MeSH
• gliom farmakoterapie   metabolismus   patologie   MeSH
• lidé MeSH
• mykotoxiny farmakologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky patologie   MeSH
• nádory mozku farmakoterapie   metabolismus   patologie   MeSH
• proteomika MeSH
• signální dráha UPR účinky léků   MeSH
• sodík metabolismus   MeSH
• vápníkové kanály - typ T fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Age-associated changes in large blood vessels were characterized by increased arterial wall thickness, luminal dilation and impaired endothelial function. But little is known about the effect of age on structural and functional changes in small resistance arteries. The mechanisms underlying age-associated endothelial dysfunction in rat mesenteric resistance arteries were investigated in the present study. Small rat mesenteric arteries were excised and cannulated, and vascular endothelial functions were tested by acetylcholine (ACh). Our experiments showed (1) endotheliumdependent vasorelaxation induced by ACh was reduced in aged mesenteric arteries; (2) blockade of Kca channels markedly reduced the vasodilation in young and adult rats, the resultant reduction in aged rats was much smaller compared with young and adult rats; (3) inhibition of endothelial nitric oxide synthase (NOS) resulted in a significant reduction of vasodilation in young and adult, but there was a smaller reduction in aged rats. The results suggest that (1) endothelial function was impaired in mesenteric arteries of aged rats; (2) both Kca channels and nitric oxide (NO) contribute together to the ACh-induced vasorelaxation in small mesenteric arteries, and (3) both the impairment of Kca channel function and decreased NO account for the age-related endothelial dysfunction.

• MeSH
• acetylcholin farmakologie   MeSH
• apamin farmakologie   MeSH
• arteriae mesentericae metabolismus   patofyziologie   účinky léků   MeSH
• blokátory draslíkových kanálů farmakologie   MeSH
• cévní endotel metabolismus   patofyziologie   účinky léků   MeSH
• charybdotoxin farmakologie   MeSH
• draslíkové kanály aktivované vápníkem antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• krysa rodu rattus MeSH
• omega-N-methylarginin farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• stárnutí metabolismus   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   metabolismus   MeSH
• techniky in vitro MeSH
• vazodilatace účinky léků   MeSH
• vazodilatancia farmakologie   MeSH
• věkové faktory MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• draslíkové kanály aktivované vápníkem antagonisté a inhibitory   fyziologie   MeSH
• draslíkové kanály řízené napětím antagonisté a inhibitory   fyziologie   MeSH
• finanční podpora výzkumu jako téma MeSH
• kotyledon fyziologie   účinky léků   MeSH
• lidé MeSH
• placentární oběh fyziologie   účinky léků   MeSH
• vazokonstrikce MeSH
• Check Tag
• lidé MeSH