Elizabeth Robinson
Preclinical evaluation of statins as a treatment for ovarian cancer
Robinson, Elizabeth; Nandi, Mandrita; Wilkinson, Laurelle L.; Arrowsmith, D. Mark; Curtis, Anthony D.M.; Richardson, Alan
Authors
Mandrita Nandi
Laurelle L. Wilkinson
D. Mark Arrowsmith
Anthony Curtis a.d.m.curtis@keele.ac.uk
Alan Richardson a.richardson1@keele.ac.uk
Abstract
Objective
To evaluate the potential for statins to treat ovarian cancer.
Methods
The sensitivity of 7 ovarian cancer cell lines to either statins or statins combined with either carboplatin or paclitaxel was assessed using monolayer cultures. Sensitivity to simvastatin was also evaluated in ovarian cancer spheroids. The kinetics of cell death induced by simvastatin was evaluated by measuring Trypan Blue exclusion. Autophagy induced by simvastatin was assessed by measuring LC3-II, p62 or Rab7 by immunoblotting or immunocytochemistry.
Results
All statins except pravastatin demonstrated single agent activity against monolayers (IC50 = 1–35 μM) and spheroids (IC50 = 1–13 μM). This was mediated by HMG-CoAR inhibition, because either mevalonate or geranylgeraniol prevented the cytotoxic effects of simvastatin. Continuous exposure for 4 days was necessary to cause cell death. Simvastatin caused accumulation of p62 but loss of Rab7, suggesting inhibition of autophagosome trafficking. Accumulation of LC3-II was also observed, even in the presence of bafilomycin, suggesting additional stimulation of an earlier step in autophagy. Knockdown of the key autophagy regulator Atg5 caused a modest increase in the sensitivity of Ovcar-8 cells to simvastatin. Finally, additive or mild antagonist effects were observed when simvastatin was combined simultaneously with either carboplatin or paclitaxel, but when cells were exposed to simvastatin prior to carboplatin, profound antagonism was observed.
Conclusions
These observations suggest that clinical trials of statins in ovarian cancer should evaluate high doses and schedules that ensure continual inhibition of HMG-CoAR. Simvastatin has conflicting effects on the autophagy pathway and this may contribute to its cytotoxic activity.
Citation
Robinson, E., Nandi, M., Wilkinson, L. L., Arrowsmith, D. M., Curtis, A. D., & Richardson, A. (2013). Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecologic Oncology, 129(2), 417-424. https://doi.org/10.1016/j.ygyno.2013.02.003
Journal Article Type | Article |
---|---|
Online Publication Date | Feb 8, 2013 |
Publication Date | 2013-05 |
Deposit Date | Jun 12, 2023 |
Journal | Gynecologic Oncology |
Print ISSN | 0090-8258 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 129 |
Issue | 2 |
Pages | 417-424 |
DOI | https://doi.org/10.1016/j.ygyno.2013.02.003 |
Keywords | Obstetrics and Gynecology; Oncology |
You might also like
Ivermectin Augments the Anti-Cancer Activity of Pitavastatin in Ovarian Cancer Cells
(2023)
Journal Article
Identification of foods that affect the anti-cancer activity of pitavastatin in cells
(2022)
Journal Article
Downloadable Citations
About Keele Repository
Administrator e-mail: research.openaccess@keele.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search