Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers
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- Shimoyama, S. Cancer Chemother Pharmacol (2011) 67: 729. doi:10.1007/s00280-011-1583-2
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Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies.
Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins.
In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies.
It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia.
KeywordsStatinsK-Ras oncogeneGastric cancerColorectal cancerMolecular targeting therapy
v-akt murine thymoma viral oncogene homolog
First-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer
Epidermal growth factor
Epidermal growth factor receptor
Extracellular signal-regulated kinase
Erbitux in combination with xeloda and cisplatin in advanced esophagogastric cancer
Leucovorin + fluorouracil + irinotecan
Leucovorin + fluorouracil + oxaliplatin
5-fluorouracil and cisplatin
Human epidermal growth factor receptor
3-hydroxy 3-methylglutaryl-coenzyme A
Human homolog of the Kirsten rat sarcoma-2 virus oncogene
Mitogen-activated protein kinase
Median survival times
Protein kinase B
Randomized controlled trials
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer
Trastuzumab for gastric cancer
Vascular endothelial growth factor