Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 4, pp 729–739

Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers

Mini Review

DOI: 10.1007/s00280-011-1583-2

Cite this article as:
Shimoyama, S. Cancer Chemother Pharmacol (2011) 67: 729. doi:10.1007/s00280-011-1583-2

Abstract

Purpose

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.

Keywords

StatinsK-Ras oncogeneGastric cancerColorectal cancerMolecular targeting therapy

Abbreviations

AKT

v-akt murine thymoma viral oncogene homolog

AVAGAST

First-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer

CRC

Colorectal cancer

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor

ERK

Extracellular signal-regulated kinase

EXPAND

Erbitux in combination with xeloda and cisplatin in advanced esophagogastric cancer

GC

Gastric cancer

FOLFIRI

Leucovorin + fluorouracil + irinotecan

FOLFOX

Leucovorin + fluorouracil + oxaliplatin

FP

5-fluorouracil and cisplatin

FTase

Farnesyltransferase

FTI

Farnesyltransferase inhibitor

GDP

Guanosine 5′-diphosphate

GGTase

Geranylgeranyltransferase

GGTI

Geranylgeranyltransferase inhibitor

GTP

Guanosine 5′-triphosphate

HER

Human epidermal growth factor receptor

HMG-CoA

3-hydroxy 3-methylglutaryl-coenzyme A

K-Ras

Human homolog of the Kirsten rat sarcoma-2 virus oncogene

MAPK

Mitogen-activated protein kinase

MSTs

Median survival times

PI3K

Phosphatidylinositol 3-kinase

PKB

Protein kinase B

RCTs

Randomized controlled trials

Rho

Ras-homologous

SPIRITS

S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer

ToGA

Trastuzumab for gastric cancer

VEGF

Vascular endothelial growth factor

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Gastrointestinal Unit, Settlement ClinicTokyoJapan