Effects of metformin on retinoblastoma growth in vitro and in vivo

View/ Open
Author
THEODOROPOULOU, SOFIA
HÖRSTE, MELISSA MEYER ZU
PASCHALIS, ELEFTHERIOS I.
TAKEUCHI, KIMIO
SCOTT, GORDON
RAMSEY, DAVID J.
KIERNAN, ELIZABETH
CICHY, JOANNA
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.3892/ijo.2014.2650Metadata
Show full item recordCitation
BRODOWSKA, K., S. THEODOROPOULOU, M. M. Z. HÖRSTE, E. I. PASCHALIS, K. TAKEUCHI, G. SCOTT, D. J. RAMSEY, et al. 2014. “Effects of metformin on retinoblastoma growth in vitro and in vivo.” International Journal of Oncology 45 (6): 2311-2324. doi:10.3892/ijo.2014.2650. http://dx.doi.org/10.3892/ijo.2014.2650.Abstract
Recent studies suggest that the anti-diabetic drug metformin may reduce the risk of cancer and have anti-proliferative effects for some but not all cancers. In this study, we examined the effects of metformin on human retinoblastoma cell proliferation in vitro and in vivo. Two different human retinoblastoma cell lines (Y79, WERI) were treated with metformin in vitro and xenografts of Y79 cells were established in nu/nu immune-deficient mice and used to assess the effects of pharmacological levels of metformin in vivo. Metformin inhibited proliferation of the retinoblastoma cells in vitro. Similar to other studies, high concentrations of metformin (mM) blocked the cell cycle in G0–G1, indicated by a strong decrease of G1 cyclins, especially cyclin D, cyclin-dependent kinases (4 and 6), and flow cytometry assessment of the cell cycle. This was associated with activation of AMPK, inhibition of the mTOR pathways and autophagy marker LC3B. However, metformin failed to suppress growth of xenografted tumors of Y79 human retinoblastoma cells in nu/nu mice, even when treated with a maximally tolerated dose level achieved in human patients. In conclusion, suprapharmacological levels (mM) of metformin, well above those tolerated in vivo, inhibited the proliferation of retinoblastoma cells in vitro. However, physiological levels of metformin, such as seen in the clinical setting, did not affect the growth of retinoblastoma cells in vitro or in vivo. This suggests that the potential beneficial effects of metformin seen in epidemiological studies may be limited to specific tumor types or be related to indirect effects/mechanisms not observed under acute laboratory conditions.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215581/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347612
Collections
- HMS Scholarly Articles [17714]
Contact administrator regarding this item (to report mistakes or request changes)