title: Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gastrointestinal Unit, Settlement Clinic, 4-20-7, Towa, Adachi-ku, Tokyo 120-0003, Japan. shimoyama@apost.plala.or.jp
authors.forename: Shouji
authors.initials: S
authors.lastname: Shimoyama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051381:Rats; D013534:Survival
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors