Send Orders for Reprints to reprints@benthamscience.net Mini-Reviews in Medicinal Chemistry, 2014, 14, 000-000 1 1389-5575/14 $58.00+.00 © 2014 Bentham Science Publishers [6]-gingerol as a Cancer Chemopreventive Agent: A Review of Its Activity on Different Steps of the Metastatic Process Juliana Poltronieri 1 , Amanda B. Becceneri 1 , Angelina M. Fuzer 1 , Julio Cesar C. Filho 1 , Ana Carolina B.M. Martin 2 , Paulo Cézar Vieira 3 , Normand Pouliot 4,5 and Márcia R. Cominetti 1 * 1 Departamento de Gerontologia, Universidade Federal de São Carlos, São Carlos, SP, Brazil; 2 Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, SP, Brazil; 3 Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil; 4 Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; 5 Sir Peter MacCallum Department of Oncology and Pathology Department, The University of Melbourne, VIC, Australia Abstract: For many years, ginger or ginger root, the rhizome of the plant Zingiber officinale, has been consumed as a delicacy, medicine, or spice. Several studies have been conducted on the medicinal properties of ginger against various disorders, including cancer. Cancer is the second leading cause of death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer initiation or progression. Evidence that ginger-derived compounds have inhibitory effects on various cancer cell types is increasingly being reported in the scientific literature. In this review we focused on the cancer chemopreventive effects of [6]-gingerol, the major pungent component of ginger, and its impact on different steps of the metastatic process. Keywords: Apoptosis, cancer, ginger, 6-gingerol, metastasis, natural product. INTRODUCTION Ginger (Zingiber officinale Roscoe, Zingiberacae) is a native plant from Southeast Asia, that has been used as an important condiment and medicinal agent for more than 2500 years [1]. Several studies have been conducted on the medicinal properties of ginger against various disorders. Ginger has been demonstrated to have anti-inflammatory, hypotensive, antioxidant, antimicrobial, and antiemetic properties and to regulate cholesterol levels [2, 3]. Ginger is composed of volatile oils (flavor and aroma) and non-volatile pungent compounds. The latter include gingerols, shogaols, paradols and zingerone, which are biologically active. Gingerols are found in greater abundance in fresh ginger, and differ in their chemical structure by the length of unbranched alkyl chains [4]. Metastasis is the leading cause of cancer death and can be described as a cascade of events, each being rate-limiting and providing potential opportunities for therapeutic intervention [5]. Normal cells are transformed into tumor cells due to mutations in genes that regulate critical pathways, producing an imbalance between proliferation and cell death that eventually leads to the formation of a primary tumor. Further interactions with the stromal microenvironment surrounding tumor cells, including endothelial cells, fibroblasts, macrophages and extracellular matrix (ECM) proteins, contribute to the formation of new blood and lymphatic *Address correspondence to this author at the Departamento de Gerontologia, Universidade Federal de São Carlos, Rodovia Washington Luís, Km 235, São Carlos, SP, 13565-905, Brazil; Tel: +55 16 3306 6663; Fax; +55 16 3351 9628; E-mail: mcominetti@ufscar.br vessels [6]. These interactions facilitate tumor cell invasion of surrounding tissues, intravasation through newly formed vessels, and dissemination to other tissues, to form secondary tumors. During the metastatic process, cells must penetrate natural barriers in the microenvironment, survive in circulation as well as invade and populate a new tissue, the latter being helped by the establishment of a pre-metastatic niche [7-9]. The ECM plays a fundamental role in tumor metastasis. The ECM represents the non-cellular component of tissues, and is formed primarily of water, proteins and polysaccharides; however, its precise composition is tissue-specific [10, 11]. Cell-cell and cell-ECM interactions are important regulator of cell adhesion, migration, proliferation and survival. These processes, in turn, play critical roles during both normal physiological and pathological conditions, such as cancer and metastasis. The aim of this review is to summarize the most recent studies on the cancer chemopreventive action of [6]-gingerol. We will focus on specific steps of the metastatic process, including cell adhesion, migration, invasion and angiogenesis and describe the effects of [6]-gingerol on each of these steps. We will, in particular, discuss the chemopreventive effects of [6]-gingerol focusing on its ability to inhibit tumor cell proliferation, and to induce apoptosis or reactive oxygen species (ROS) production. This review is divided into two parts describing first results from studies performed in vitro and then in different animal models in vivo. It was prepared using publications reported over the last 10 years (2003 to 2013) on the NLM-Pubmed and TS-Web of Science online bibliographic databases, using the keyword “[6]-gingerol”