Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells |
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| Authors: | Claire Levrier Anja Rockstroh Brian Gabrielli Maria Kavallaris Melanie Lehman Rohan A Davis |
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| Institution: | 1. Australian Prostate Cancer Research Centre?Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD, Australia;2. Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia;3. The University of Queensland Diamantina Institute;4. Translational Research Institute;5. Brisbane, QLD, Australia;6. Tumour Biology and Targeting Program, Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Sydney, NSW, Australia;7. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, UNSW Australia, Sydney, NSW, Australia;8. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada |
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| Abstract: | We report for the first time the mechanism of action of the natural product thalicthuberine (TH) in prostate and cervical cancer cells. TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects, and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. However, unlike microtubule-binding drugs (vinblastine and paclitaxel), TH did not directly inhibit tubulin polymerization when tested in a cell-free system, whereas it reduced cellular microtubule polymer mass in LNCaP cells. This suggests that TH indirectly targets microtubule dynamics through inhibition of a critical regulator or tubulin-associated protein. Furthermore, TH is not a major substrate for P-glycoprotein (Pgp), which is responsible for multidrug resistance in numerous cancers, providing a rationale to further study TH in cancers with Pgp-mediated treatment resistance. The identification of TH's molecular target in future studies will be of great value to the development of TH as potential treatment of multidrug-resistant tumors. |
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| Keywords: | Thalicthuberine mitotic inhibitor microtubule dynamics tubulin polymerization prostate cancer |
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