https://scholars.lib.ntu.edu.tw/handle/123456789/543848
Title: | Repurposing of phentolamine as a potential anticancer agent against human castration-resistant prostate cancer: A central role on microtubule stabilization and mitochondrial apoptosis pathway | Authors: | Ho C.-H. Hsu J.-L. SHIH-PING LIU LIH-CHING HSU Chang W.-L. Chao C.C.-K. JIH-HWA GUH |
Issue Date: | 2015 | Publisher: | John Wiley and Sons Inc. | Journal Volume: | 75 | Journal Issue: | 13 | Start page/Pages: | 1454-1466 | Source: | Prostate | Abstract: | BACKGROUND Drug repurposing of phentolamine, an α-adrenoceptor antagonist, as an anticancer agent has been studied in human castration-resistant prostate cancer (CRPC). METHODS Cell proliferation was examined by sulforhodamine B and CFSE staining assays. Cell cycle progression and mitochondrial membrane potential (ΔΨm) were detected by flow cytometric analysis. Protein expression was detected by Western blotting. Effect on tubulin/microtubule was determined using confocal immunofluorescence microscopic examination, microtubule assembly detection, tubulin turbidity assay, and binding assay. Several assessments were used to characterize apoptotic signaling pathways and combinatory effect. RESULTS Phentolamine induced anti-proliferative effect in PC-3 and DU-145, two CRPC cell lines, and P-glycoprotein (P-gp) overexpressing cells. This effect was not significantly reduced in paclitaxel-resistant cells. Rhodamine 123 efflux assay showed that phentolamine was not a P-gp substrate. Phentolamine induced mitotic arrest of the cell cycle and formation of hyperdiploid cells, followed by an increase of apoptosis. Mitotic arrest was confirmed by cyclin B1 up-regulation, Cdk1 activation, and a dramatic increase of mitotic protein phosphorylation. Both in vitro and cellular identification demonstrated that phentolamine, similar to paclitaxel, induced tubulin polymerization and formation of multiple nuclei. Besides, it did not compete with paclitaxel binding on tubulin. Phentolamine induced the phosphorylation and degradation of Bcl-2 and Bcl-xL, two anti-apoptotic Bcl-2 family members, and the loss of ΔΨm indicating the induction of mitochondrial damage. It ultimately induced the activation of caspase-9, -8, and -3 and apoptotic cell death. Moreover, combination treatment with phentolamine and paclitaxel caused a synergistic apoptosis. CONCLUSIONS The data suggest that phentolamine is a potential anticancer agent. In contrast to a wide variety of microtubule disrupting agents, phentolamine induces microtubule assembly, leading to mitotic arrest of the cell cycle which "in turn" induces subsequent mitochondrial damage and activation of related apoptotic signaling pathways in CRPC cells. Furthermore, combination between phentolamine and paclitaxel induces a synergistic apoptotic cell death. Phentolamine has a simple chemical structure and is not a P-gp substrate. Optimization of phentolamine structure may also be a potential approach for further development. ? 2015 Wiley Periodicals, Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84939190874&doi=10.1002%2fpros.23033&partnerID=40&md5=ff05b9341ef4d5f86da4e41d8889d5d7 https://scholars.lib.ntu.edu.tw/handle/123456789/543848 |
ISSN: | 0270-4137 | DOI: | 10.1002/pros.23033 | SDG/Keyword: | caspase 3; caspase 8; caspase 9; cyclin B1; cyclin dependent kinase 1; multidrug resistance protein; nocodazole; paclitaxel; phentolamine; protein bcl 2; protein bcl xl; tubulin; vincristine; antineoplastic agent; phentolamine; antiproliferative activity; apoptosis; Article; castration resistant prostate cancer; cell cycle progression; cell proliferation; concentration response; controlled study; drug effect; drug potentiation; drug protein binding; drug repositioning; enzyme activation; G2 phase cell cycle checkpoint; human; IC50; in vitro study; microtubule; microtubule assembly; mitochondrial membrane potential; mitochondrion; mitosis inhibition; multinuclear cell; priority journal; prostate cancer cell line; protein degradation; protein expression; protein phosphorylation; signal transduction; upregulation; apoptosis; cell cycle; drug effects; drug repositioning; male; metabolism; microtubule; mitochondrion; pathology; Prostatic Neoplasms, Castration-Resistant; tumor cell line; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Repositioning; Humans; Male; Membrane Potential, Mitochondrial; Microtubules; Mitochondria; Phentolamine; Prostatic Neoplasms, Castration-Resistant |
Appears in Collections: | 醫學系 |
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