15357163mct150800-sup-156259_3_video_3499046_f7c9dn.avi (2.47 MB)
Movie S2 from ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme
mediaposted on 2023-04-03, 14:48 authored by Allison E. Cherry, Brian R. Haas, Alipi V. Naydenov, Susan Fung, Cong Xu, Katie Swinney, Michael Wagenbach, Jennifer Freeling, David A. Canton, Jonathan Coy, Eric A. Horne, Barry Rickman, Juan Jesus Vicente, John D. Scott, Rodney J.Y. Ho, Denny Liggitt, Linda Wordeman, Nephi Stella
The same T98G cell that is shown in Movie S1 imaged 10 min after the addition of 0.5 ÂµM ST-11. Speed = 10Ã-.
ARTICLE ABSTRACTGlioblastoma 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.
Cell CycleControl of cell cycle progressionCns CancersDrug MechanismsCell cycle mechanisms of anticancer drug actionCellular responses to anticancer drugsPharmacologyCellular pharmacologyMolecular pharmacologyPharmacokinetics and pharmacodynamicsPreclinical ModelsXenograft modelsSmall Molecule Agents