Discovery of thalicthuberine as a novel antimitotic agent from nature that disrupts microtubule dynamics and induces apoptosis in prostate cancer cells
| Autor: | Martin C. Sadowski, Rohan A. Davis, Melanie Lehman, Claire Levrier, Colleen C. Nelson, Brian Gabrielli, Anja Rockstroh, Maria Kavallaris |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Mitosis Apoptosis Spindle Apparatus Antimitotic Agents Biology Microtubules 03 medical and health sciences chemistry.chemical_compound Alkaloids 0302 clinical medicine Tubulin Microtubule Cell Line Tumor LNCaP medicine Humans Thalicthuberine ATP Binding Cassette Transporter Subfamily B Member 1 Molecular Biology Mitotic catastrophe Aurora Kinase A Cell Proliferation Prostatic Neoplasms Cell Biology Phenanthrenes microtubule dynamics prostate cancer G1 Phase Cell Cycle Checkpoints 3. Good health Mitotic inhibitor Cell biology Vinblastine Gene Expression Regulation Neoplastic tubulin polymerization 030104 developmental biology Paclitaxel chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Antimitotic Agent mitotic inhibitor Reports Developmental Biology medicine.drug |
| Zdroj: | Cell Cycle |
| ISSN: | 1551-4005 1538-4101 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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