ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme.

Autor:	Cherry AE; Department of Pharmacology, University of Washington, Seattle, Washington., Haas BR; Department of Pharmacology, University of Washington, Seattle, Washington., Naydenov AV; Department of Pharmacology, University of Washington, Seattle, Washington. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington., Fung S; Department of Pharmacology, University of Washington, Seattle, Washington. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington., Xu C; Department of Pharmacology, University of Washington, Seattle, Washington., Swinney K; Department of Pharmacology, University of Washington, Seattle, Washington., Wagenbach M; Department of Physiology and Biophysics, University of Washington, Seattle, Washington., Freeling J; Department of Pharmaceutics, University of Washington, Seattle, Washington., Canton DA; Department of Pharmacology, University of Washington, Seattle, Washington. Howard Hughes Medical Institute, University of Washington, Seattle, Washington., Coy J; Department of Pharmacology, University of Washington, Seattle, Washington., Horne EA; Department of Pharmacology, University of Washington, Seattle, Washington., Rickman B; Department of Comparative Medicine, University of Washington, Seattle, Washington., Vicente JJ; Department of Physiology and Biophysics, University of Washington, Seattle, Washington., Scott JD; Department of Pharmacology, University of Washington, Seattle, Washington. Howard Hughes Medical Institute, University of Washington, Seattle, Washington., Ho RJ; Department of Pharmaceutics, University of Washington, Seattle, Washington., Liggitt D; Department of Comparative Medicine, University of Washington, Seattle, Washington., Wordeman L; Department of Physiology and Biophysics, University of Washington, Seattle, Washington., Stella N; Department of Pharmacology, University of Washington, Seattle, Washington. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington. nstella@uw.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Sep; Vol. 15 (9), pp. 2018-29. Date of Electronic Publication: 2016 Jun 20.
DOI:	10.1158/1535-7163.MCT-15-0800
Abstrakt:	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. Competing Interests: Authors disclose no conflict of interest. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu