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A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells Claire Levrier1,2, Martin C

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Published OnlineFirst October 19, 2016; DOI: 10.1158/1535-7163.MCT-16-0325 Small Molecule Therapeutics Molecular Cancer Therapeutics 6a-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells Claire Levrier1,2, Martin C. Sadowski1, Anja Rockstroh1, Brian Gabrielli3, Maria Kavallaris4,5, Melanie Lehman1,6, Rohan A. Davis2, and Colleen C. Nelson1 Abstract The lack of a cure for metastatic castrate-resistant prostate cer drug vinblastine, which included pathways involved in mito- cancer (mCRPC) highlights the urgent need for more efficient sis, microtubule spindle organization, and microtubule binding. drugs to fight this disease. Here, we report the mechanism of Like vinblastine, 6-AA inhibited microtubule polymerization action of the natural product 6a-acetoxyanopterine (6-AA) in in a cell-free system and reduced cellular microtubule polymer prostate cancer cells. At low nanomolar doses, this potent cyto- mass. Yet, microtubule alterations that are associated with resis- toxic alkaloid from the Australian endemic tree Anopterus tance to microtubule-destabilizing drugs like vinca alkaloids macleayanus induced a strong accumulation of LNCaP and PC- (vinblastine/vincristine) or 2-methoxyestradiol did not confer 3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in resistance to 6-AA, suggesting a different mechanism of microtu- mitosis, severe mitotic spindle defects, and asymmetric cell divi- bule interaction. 6-AA is a first-in-class microtubule inhibitor that sions, ultimately leading to mitotic catastrophe accompanied by features the unique anopterine scaffold. This study provides a cell death through apoptosis. DNA microarray of 6-AA–treated strong rationale to further develop this novel structure class LNCaP cells combined with pathway analysis identified very of microtubule inhibitor for the treatment of malignant disease. similar transcriptional changes when compared with the antican- Mol Cancer Ther; 16(1); 3–15. Ó2016 AACR. Introduction lenged by known resistance pathways (2). The majority of anti- cancer drugs currently in use are natural products, natural product Prostate cancer is the second most diagnosed cancer in men in derivatives, or compounds developed on the basis of a natural developed countries and the fifth most common cause for cancer- product pharmacophore (3). Numerous organisms of various related deaths (1). Metastatic castrate-resistant prostate cancer biota independently developed a great diversity of natural pro- (mCRPC) remains an incurable disease despite the recent ducts throughout evolution as antipredatory defenses based on approvals of new and more efficacious therapeutics (2). This targeting microtubule dynamics (4). Microtubules are crucial for highlights the need for additional prostate cancer therapies, for cellular processes, such as cell division, mobility, intracellular example, drugs that inhibit proven targets, yet remain unchal- organelle transport, and endothelial cell biology (angiogenesis; ref. 5). Microtubules are highly dynamic protein structures, which continuously undergo growth through polymerization and 1Australian Prostate Cancer Research CentreÀQueensland, School of Biomed- shrinkage through depolymerization of a- and b-tubulin hetero- ical Sciences, Institute of Health and Biomedical Innovation, Queensland Uni- dimers (microtubule dynamics; ref. 6). In mitosis, microtubules versity of Technology, Princess Alexandra Hospital, Translational Research play a vital role in the assembly of the spindle apparatus and 2 Institute, Brisbane, Australia. Eskitis Institute for Drug Discovery, Griffith proper segregation of chromosomes to both daughter cells (6). University, Brisbane, Australia. 3Translational Research Institute, The University 4 This critical function has been successfully exploited for the of Queensland Diamantina Institute, Brisbane, Australia. Tumour Biology and fi Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, development of anticancer drugs and is exempli ed by the semi- University of New South Wales Australia, New South Wales, Australia. 5ARC synthetic taxanes docetaxel and cabazitaxel, which are the FDA- Centre of Excellence in Convergent Bio-Nano Science and Technology and approved mainstay therapies of mCRPC (2). Vinca alkaloids (e.g., Australian Centre for NanoMedicine, University of New South Wales Australia, the natural products vinblastine, vincristine, and semisynthetic 6 New South Wales, Australia. Department of Urologic Sciences, Vancouver vinorelbine) are another class of microtubule inhibitors currently Prostate Centre, University of British Columbia, Vancouver, Canada. used as gold standards in chemotherapy for Hodgkin disease, Note: Supplementary data for this article are available at Molecular Cancer non-Hodgkin lymphoma, and breast cancer (6). At clinically Therapeutics Online (http://mct.aacrjournals.org/). relevant doses (low nanomolar), both drug classes kinetically Corresponding Author: Colleen C. Nelson, Queensland University of Technol- stabilize the microtubules, without changing microtubule poly- ogy, Translational Research Institute, Princess Alexandra Hospital, Brisbane, mer mass (7–9). This leads to mitotic arrest at the metaphase– Queensland 4102, Australia. Phone: 61-7-3176-7443; Fax: 61-7-3176-7440; anaphase transition, chromosome missegregation, genome insta- E-mail: [email protected] bility, and ultimately mitotic catastrophe and cell death (6). At doi: 10.1158/1535-7163.MCT-16-0325 higher concentrations (micromolar), taxanes stabilize microtu- Ó2016 American Association for Cancer Research. bules through binding to the taxane-binding site on b-tubulin www.aacrjournals.org 3 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 19, 2016; DOI: 10.1158/1535-7163.MCT-16-0325 Levrier et al. (10). Vinca alkaloids bind to the vinca domain on b-tubulin and Assessment of cell viability and proliferation induce microtubule depolymerization (11). Another class of LNCaP (4,000 cells/well), HeLa (2,000 cells/well), and PC-3 microtubule destabilizers includes the natural products colchi- (3,000 cells/well) cells were seeded in 96-well plates and allowed cine, combretastatins, and 2-methoxyestradiol (2ME2), which all to attach for 24 hours. Cell viability as a function of metabolic interact with the colchicine domain located at the intradimer activity was measured by alamarBlue endpoint assay (Thermo interface between a/b-tubulin heterodimers, leading to microtu- Fisher Scientific) after 72 hours of treatment (20). Nonadherent bule depolymerization (12). Since the development of vinblas- T-ALL cell lines (20,000 cells/well) were simultaneously seeded in tine and paclitaxel, other natural product–derived microtubule 96-well plates and treated with the indicated compounds for 72 inhibitors have reached the market. Sagopilone (epothilone ana- hours. Cell proliferation as a function of cell confluence was logue, stabilizer) has shown very promising results in a phase II evaluated using live-cell imaging (IncuCyte, Essen BioScience) clinical trial in mCRPC (13). The FDA-approved microtubule- as described before (20). depolymerizing agent eribulin has shown activity in a phase II clinical trial (14). Despite their initial therapeutic success, resis- Cell-cycle analysis by flow cytometry tance to these agents develops. Known resistance mechanisms LNCaP cells were plated in 6-well plates (150,000 cells/well), induced by microtubule inhibitors include drug efflux through allowed to attach for 24 hours, and treated with the indicated increased expression of multidrug resistance transporters, tubulin compounds for 24 hours. Cell-cycle experiments were conducted isoform expression, and mutations (6). We have previously as described previously (21). Samples were analyzed on a FACS- reported the identification and cytotoxicity analysis of eight Canto (BD Biosciences). DNA histograms were analyzed using C diterpenoid alkaloids that feature the unique anopterine 20 ModFit LT software (Verity Software House). scaffold from the Australian endemic rainforest plant Anopterus macleayanus (15). The anopterine analogues induced cell death in a panel of prostate cancer cell lines at nanomolar concentrations Wound closure assay (15). Here, we present the mechanism-of-action studies of the PC-3 cells (30,000 cells/well) were seeded in 96-well Image- most potent anopterine analogue, 6a-acetoxyanopterine (6-AA) Lock plates (Essen BioScience) and allowed to attach for 24 hours. and provide evidence that the anopterine scaffold represents a Wounds were generated with a 96-well mechanical Woundmaker novel structure class of microtubule inhibitors with a mechanism (Essen BioScience); cells were treated with the indicated com- of interaction that is distinct to taxanes, vinca alkaloids, and pounds for 16 hours. Wound closure was measured using a live- 2-methoxyestradiol. This is the first time that such activity has cell imaging system (IncuCyte) according to the manufacturer's been described for this structure class. instructions (Essen BioScience). Materials and Methods Microarray gene expression profiling LNCaP cells were seeded and allowed to attach for 24 hours in a Reagents Vinblastine, colchicine, nocodazole, verapamil, 2-methoxyes- 6-well plate (150,000 cells/well) then treated with 6-AA (10 nmol/L) or vinblastine (3.25 nmol/L) for 24 hours before RNA tradiol (all Sigma-Aldrich),
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