6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells

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 po...

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Published inMolecular cancer therapeutics Vol. 16; no. 1; pp. 3 - 15
Main Authors Levrier, Claire, Sadowski, Martin C, Rockstroh, Anja, Gabrielli, Brian, Kavallaris, Maria, Lehman, Melanie, Davis, Rohan A, Nelson, Colleen C
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research Inc 01.01.2017
Subjects
Alkaloids
Antimitotic Agents - chemistry
Antimitotic Agents - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Biological Products - chemistry
Biological Products - pharmacology
Cancer
Cell Cycle - drug effects
Cell death
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cell-free system
Cervical cancer
Cervix
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA microarrays
Drug resistance
Drugs
Gene Expression Profiling
Humans
Inhibitors
Male
Medical treatment
Metastases
Microtubules - metabolism
Mitosis
Mitosis - drug effects
Mitosis - genetics
Polymerization
Prostate cancer
Prostatic Neoplasms - metabolism
Protein Multimerization - drug effects
Spindle Apparatus - drug effects
Transcription
Tubulin - chemistry
Tubulin - metabolism
Tubulin Modulators - chemistry
Tubulin Modulators - pharmacology
Vinblastine
Vinblastine - pharmacology
Vincristine
Online AccessGet full text

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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. ©2016 AACR.
AbstractList 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.
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.
Author Rockstroh, Anja
Lehman, Melanie
Gabrielli, Brian
Davis, Rohan A
Sadowski, Martin C
Kavallaris, Maria
Levrier, Claire
Nelson, Colleen C
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  organization: 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
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  givenname: Anja
  surname: Rockstroh
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  organization: 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
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  surname: Nelson
  fullname: Nelson, Colleen C
  email: colleen.nelson@qut.edu.au
  organization: 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
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Snippet 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,...
Abstract The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this...
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SubjectTerms Alkaloids
Antimitotic Agents - chemistry
Antimitotic Agents - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Biological Products - chemistry
Biological Products - pharmacology
Cancer
Cell Cycle - drug effects
Cell death
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cell-free system
Cervical cancer
Cervix
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA microarrays
Drug resistance
Drugs
Gene Expression Profiling
Humans
Inhibitors
Male
Medical treatment
Metastases
Microtubules - metabolism
Mitosis
Mitosis - drug effects
Mitosis - genetics
Polymerization
Prostate cancer
Prostatic Neoplasms - metabolism
Protein Multimerization - drug effects
Spindle Apparatus - drug effects
Transcription
Tubulin - chemistry
Tubulin - metabolism
Tubulin Modulators - chemistry
Tubulin Modulators - pharmacology
Vinblastine
Vinblastine - pharmacology
Vincristine
Title 6α-Acetoxyanopterine: A Novel Structure Class of Mitotic Inhibitor Disrupting Microtubule Dynamics in Prostate Cancer Cells
URI https://www.ncbi.nlm.nih.gov/pubmed/27760837
https://www.proquest.com/docview/1983851008
https://search.proquest.com/docview/1835504555
Volume 16
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