166728_1_video_3626510_8bxsn8.avi (2.04 MB)
Supplementary Video S5. Interphase microtubule dynamics in HeLa-EB1-GFP treated with vinblastine (20 nM). from 6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells
mediaposted on 2023-04-03, 15:43 authored by Claire Levrier, Martin C. Sadowski, Anja Rockstroh, Brian Gabrielli, Maria Kavallaris, Melanie Lehman, Rohan A. Davis, Colleen C. Nelson
EB1-GFP was imaged by spinning disk microscopy (2 images/s for 2 min). EB1 comets appeared faint and followed irregular and short trajectories. Scale bar=10 Âµm.
Australian Government Department of Health
Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology
Australian Research Council
ARTICLE ABSTRACTThe lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA–treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. Mol Cancer Ther; 16(1); 3–15. ©2016 AACR.
Computational MethodsGene expression profilingDrug Discovery TechnologiesNatural productsDrug MechanismsCell cycle mechanisms of anticancer drug actionCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysGenitourinary CancersProstate cancerSmall Molecule AgentsTubulin agents