dc.contributor.author | LAWLER, MARK | |
dc.contributor.author | WILLIAMS, DAVID CLIVE | |
dc.contributor.author | NATHWANI, SEEMA | |
dc.contributor.author | MEEGAN, MARY JANE | |
dc.contributor.author | ZISTERER, DANIELA MARIA | |
dc.date.accessioned | 2010-09-16T12:34:20Z | |
dc.date.available | 2010-09-16T12:34:20Z | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010 | en |
dc.identifier.citation | Nathwani, S-M., Butler, S., Meegan, M.J., Campiani, G., Lawler, M., Williams, D.C. & Zisterer, D.M., Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines., Cancer Chemotherapy and Pharmacology, 65, 2, 2010, 289-300 | en |
dc.identifier.other | Y | |
dc.identifier.uri | http://hdl.handle.net/2262/40659 | |
dc.description | PUBLISHED | en |
dc.description.abstract | Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tends to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce anti-proliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G2/M arrest. G2/M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of anti-apoptotic proteins Bcl-2 and Bcl-xL and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G2/M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-xL. Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOX-induced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer. | en |
dc.description.sponsorship | This project was kindly funded by The Irish Cancer Society and Science Foundation Ireland.
We thank Dr. Orla Hanrahan for her assistance with the fluorescence microscopy. | en |
dc.format.extent | 289-300 | en |
dc.language.iso | en | en |
dc.publisher | Springer | en |
dc.relation.ispartofseries | Cancer Chemotherapy and Pharmacology; | |
dc.relation.ispartofseries | 65; | |
dc.relation.ispartofseries | 2; | |
dc.rights | Y | en |
dc.subject | Biochemistry | en |
dc.subject | Oncology | en |
dc.subject | PBOX | en |
dc.subject | microtubule-targeting agents | en |
dc.subject | flavopiridol | en |
dc.subject | prostate cancer | en |
dc.title | Dual targeting of tumour cells and host endothelial cells by novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines. | en |
dc.type | Journal Article | en |
dc.contributor.sponsor | Enterprise Ireland | en |
dc.contributor.sponsor | Science Foundation Ireland | |
dc.type.supercollection | scholarly_publications | en |
dc.type.supercollection | refereed_publications | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/dzistrer | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/mplawler | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/dwillims | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/nathwans | |
dc.identifier.peoplefinderurl | http://people.tcd.ie/mmeegan | |
dc.identifier.rssinternalid | 57843 | |
dc.identifier.rssuri | http://dx.doi.org/10.1007/s00280-009-1033-6 | en |