title: 6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells.
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. ©2016 AACR.
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.|Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Levrier
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Sadowski
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.
authors.forename: Anja
authors.initials: A
authors.lastname: Rockstroh
authors.affiliation: Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
authors.affiliation: Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, New South Wales, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia.|Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lehman
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Australia.
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Australia. colleen.nelson@qut.edu.au.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
mesh_terms: D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D001688:Biological Products; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine