Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

Teiti Iotefa,Sarrabayrouse Guillaume

doi:10.4172/2471-9552.1000111

Abstract

Statins, 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are pleiotropic pharmacological inhibitors, which block the mevalonate synthesis pathway. They are widely used as hypocholesterolemic agents and have shown protective effects against cancers. Our previous data showed that statin treatment induced MHC class I chain-related protein A (MICA) membrane overexpression in human melanoma cells, which increased their sensitivity to NK cell cytotoxicity and thus the inhibition of tumor development. MICA is a ligand of the NK cell activating receptor NKG2D. This receptor is essential for NK cell control of tumor development and it has the unique property of being able to recognize tumor cells of both murine and human origin. Here, using atorvastatin and the WM-266-4 melanoma cell line, we first confirmed that statin treatment enhances MICA membrane expression and decreases local tumor growth and pulmonary metastasis implantation in vivo. Furthermore our new experiments showed that atorvastatin intraperitoneal repeated injections induced a reduction of tumor growth following subcutaneous implantation of untreated WM 266-4 cells into NMRI nude mice and favored the innate anti-melanoma immune response by increasing splenic NK cell concentration and activation. This report confirms that statins could become effective pharmacological agents for melanoma immunotherapy.

Highlights

Despite tumor antigen expression in human melanoma cells and the mobilization of an immune response in patients, survival after metastasis detection is usually short [1]
We have previously shown that the in vitro treatment of human melanoma cells with atorvastatin or lovastatin enhanced tumor membrane expression of the MHC class I chain-related protein A (MICA), which is a ligand of the NKG2D activating receptor of NK cells [6,7,8]
NKG2D can recognize tumor cells of both murine and human origin [10]. This unique property allowed us to show that the statin-induced MICA membrane overexpression enhanced in vitro melanoma sensitivity to NK cell lysis and decreased local tumor growth and pulmonary metastasis implantation in mice injected with statin-treated melanoma cells [6]

Summary

Introduction

Despite tumor antigen expression in human melanoma cells and the mobilization of an immune response in patients, survival after metastasis detection is usually short [1]. We have previously shown that the in vitro treatment of human melanoma cells with atorvastatin or lovastatin enhanced tumor membrane expression of the MHC class I chain-related protein A (MICA), which is a ligand of the NKG2D activating receptor of NK cells [6,7,8]. This effect is important because NKG2D expression is essential for NK cell control of tumor development [9]. This report provides further evidence that statins could become interesting pharmacological agents for melanoma immunotherapy

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