dc.contributor.author |
Leung, Yee Fun |
en |
dc.contributor.author |
Rewcastle, Gordon |
en |
dc.contributor.author |
Joseph, Wayne |
en |
dc.contributor.author |
Rosengren, RJ |
en |
dc.contributor.author |
Larsen, L |
en |
dc.contributor.author |
Baguley, Bruce |
en |
dc.date.accessioned |
2012-02-28T06:44:41Z |
en |
dc.date.issued |
2012 |
en |
dc.identifier.citation |
Investigational New Drugs 30(6):2103-2112 |
en |
dc.identifier.issn |
0167-6997 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/12219 |
en |
dc.description.abstract |
Breast cancer is commonly treated with anti-estrogens or aromatase inhibitors, but resistant disease eventually develops and new therapies for such resistance are of great interest. We have previously isolated several tamoxifen-resistant variant sub-lines of the MCF-7 breast cancer cell line and provided evidence that they arose from expansion of pre-existing minor populations. We have searched for therapeutic agents that exhibit selective growth inhibition of the resistant lines and here investigate 2,6-bis(pyridin-3-ylmethylene)-cyclohexanone (RL90) and 2,6-bis(pyridin-4-ylmethylene)-cyclohexanone (RL91). We found that two of the tamoxifen-resistant sub-lines (TamR3 and TamC3) unexpectedly showed increased sensitivity to RL90 and RL91. We utilized growth inhibition assays, flow cytometry and immunoblotting to establish a mechanistic basis for their action. Treated sensitive cells showed S-phase selective DNA damage, as detected by histone H2AX phosphorylation. Cellular responses were similar to those induced by the topoisomerase I poison camptothecin. Although IC(50) values of camptothecin, RL90, RL91 were correlated, studies with purified mammalian topoisomerase I suggested that RL90 and RL91 differed from camptothecin by acting as catalytic topoisomerase I inhibitors. These drugs provide a platform for the further development of DNA damaging drugs that have selective effects on tamoxifen resistant breast cancer cells. The results also raise the question of whether clinical topoisomerase I poisons such as irinotecan and topotecan might be active in the treatment of some types of tamoxifen-resistant cancer. |
en |
dc.language |
ENG |
en |
dc.publisher |
The Author(s) |
en |
dc.relation.ispartofseries |
Investigational New Drugs |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1007/s10637-011-9768-4 |
en |
pubs.issue |
6 |
en |
pubs.begin-page |
2103 |
en |
pubs.volume |
30 |
en |
dc.rights.holder |
Copyright: The Author(s) |
en |
dc.identifier.pmid |
22105790 |
en |
pubs.end-page |
2112 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
244821 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1573-0646 |
en |
pubs.record-created-at-source-date |
2011-12-02 |
en |
pubs.online-publication-date |
2011-11-22 |
en |
pubs.dimensions-id |
22105790 |
en |