6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells
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Sadowski, Martin C
Rockstroh, Anja
Gabrielli, Brian
Kavallaris, Maria
Lehman, Melanie
Davis, Rohan A
Nelson, Colleen C
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Abstract
The 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.
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Molecular Cancer Therapeutics
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© 2017 AACR. This is the author-manuscript version of the paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal link for access to the definitive, published version.
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Oncology and carcinogenesis
Oncology and carcinogenesis not elsewhere classified
Pharmacology and pharmaceutical sciences
Mitotic inhibitor
Microtubule dynamics
Prostate cancer cells