Format

Send to

Choose Destination
Br J Cancer. 2014 Oct 14;111(8):1562-71. doi: 10.1038/bjc.2014.431. Epub 2014 Aug 5.

In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells.

Author information

1
Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
2
Departments of Bioengineering and Medicine and Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA.
3
Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
4
1] Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA [2] Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.

Abstract

BACKGROUND:

The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk.

METHODS:

We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations.

RESULTS:

In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells.

CONCLUSIONS:

Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.

PMID:
25093497
PMCID:
PMC4200085
DOI:
10.1038/bjc.2014.431
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center