Elsevier

Biochemical Pharmacology

Volume 84, Issue 10, 15 November 2012, Pages 1268-1276
Biochemical Pharmacology

Review
Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

https://doi.org/10.1016/j.bcp.2012.07.015Get rights and content

Abstract

Phytochemicals and their synthetic derivatives are making a significant contribution in modern drug discovery programs by targeting several human diseases, including cancer. Most of these natural compounds are often multitargeted in nature, which is generally a very desirable property for cancer therapy, as carcinomas typically involve dysregulation of multiple genes and associated cell-signaling pathways at various stages of initiation, progression and metastasis. Additionally, these natural agents generally have lower side-effects, are readily available and hence are cost effective. One such natural compound is zerumbone, a cyclic eleven-membered sesquiterpene, isolated from the tropical plant Zingiber zerumbet Smith that has attracted great attention recently for its potent anticancer activities in several tumor models. This review summarizes the data based on various in vitro and in vivo studies related to the effects of zerumbone on numerous pivotal molecular targets in cancer and its reported chemopreventive/therapeutic effects in different models of cancer.

Introduction

Plant-derived natural products or ‘phytochemicals’ have been used for medicinal purposes for millennia [1], [2], [3], [4]. Many ancient civilizations used edible plants, parts of plants and plant extracts for treating several human ailments [5], [6], [7]. With developments in modern science and technology, isolation of bioactive components from natural sources and identification of their molecular mechanism of action in the living system became an important pharmacological research [8], [9], [10]. Several promising natural products and natural product-inspired compounds are currently in clinical and pre-clinical developmental stages for cancer treatment [7], [11], [12], [13]. Limited supply of active compounds from natural sources, difficulties in complete profiling of their cellular targets and characterization of their molecular mechanisms of action are among the key challenges in the natural product-based drug discovery programs [4], [14]. Developments of ingenious approaches such as metabolic engineering and synthetic biology [6], [15], [16], [17] are expected to provide solutions to maximize the production of important bio-active components. However, there is still an urgent need to accelerate the target profiling of various isolated natural compounds.

Interestingly, phytochemicals exhibit their anti-cancer properties via a variety of distinct mechanisms [18], [19], [20]. For instance, some act as cancer blocking agents, which essentially facilitate the detoxification of specific pro-carcinogens so that their activation to lethal carcinogens is prevented [19], [21]. Others act as cancer suppressing agents, and can inhibit the development of cancer-initiated cells to pre-neoplastic and neoplastic cells [22], [23]. However, in most cases, a given phytochemical can execute a multitude of intracellular effects, rather than a specific biological interaction, and the combination of these effects eventually facilitates cancer prevention/treatment [24], [25]. Many phytochemicals are also found to modulate inflammation-related molecular targets [26], [27]. Inflammation is a complex, multifunctional biological response of vascular tissues to tissue injury, characterized at the molecular level by the formation of a network of chemical signals that activate and direct migration of leukocytes from the venous system to the sites of injury [19], [28]. While acute inflammation is an immediate response to injury, chronic inflammation leads to cellular environments with significant neoplastic risk [21], [29], [30]. Numerous cellular molecules serve as biomarkers of inflammation. These include pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1α, IL-1β, chemokine CXC chemokine receptor 4 (CXCR4) and its ligand CXCL12, interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and endothelial leukocyte adhesion molecule (ELAM) and angiogenic factors such as vascular endothelial growth factor (VEGF) [31], [32], [33]. As the functional and causal relationship of inflammation with several carcinomas becomes more evident in recent years, agents that are found to modulate inflammation-related molecular targets are receiving substantial interest in anti-cancer drug development programs.

Among the various secondary metabolites (such as terpenoids, alkaloids, phenolic compounds, and glycosides) isolated from different plant sources, the terpenoids, obtained from the modification of basic five-carbon isoprene backbone units, form the largest class with more than 25,000 members identified so far [34], [35]. According to the number of isoprene units in their backbone, the terpenoids are classified into hemiterpinoids (one isoprene unit, 5C), monoterpinoids (two isoprene units, 10C), sesquiterpinoids (three isoprene units, 15C), diterpinoids (four isoprene units, 20C), sesterterpinoid (five isoprene unit, 25C) and so on [36]. Many terpenoids show therapeutic potential as anti-bacterial [37], anti-viral [38], anti-malarial [39], anti-parasitic [40], anti-hyperglycemic [41], anti-inflammatory [42] and anti-cancer agents [36]. One such terpenoid compound that holds tremendous potential for the prevention/treatment of cancer is zerumbone (2,6,9,9-tetramethyl-[2E,6E,10E]-cycloundeca-2,6,10-trien-1-one), a cyclic eleven-membered sesquiterpene, isolated from the rhizomes of the tropical plant Zingiber zerumbet Smith. Although the exact molecular mechanism(s) for the potential anti-cancer effects of zerumbone remains yet to be elucidated, existing literature suggests that it can modulate an array of important molecular targets both for the prevention and treatment of cancer (Fig. 1). In this minireview, we summarize the data from published literature on the reported in vitro and in vivo anti-cancer effects of zerumbone thereby, highlighting its potential therapeutic role in different cancers.

Section snippets

Reported in vitro anti-cancer effects of zerumbone

In vitro studies using a variety of cancer cell lines have so far provided important clues into the potential molecular targets of zerumbone. Murakami and co-workers reported concentration-dependent suppressive effect of zerumbone on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced superoxide anion radical (O2) generation from both nicotinamide adenine dinucleotide phosphate oxidase in differentiated HL-60 cells and xanthine oxidase in AS52 CHO cells [43]. In both cases, complete abrogation

In vivo anti-cancer effects of zerumbone

Zerumbone has been reported to inhibit tumor growth in various animal models of inflammation and cancer (Table 2). In the first published in vivo study with zerumbone, Tanaka and co-workers reported that oral administration of the sesquiterpene suppressed azoxymethane-induced colonic aberrant crypt foci in male F344 rats in a dose-dependent manner [64]. Subsequently, Murakami and co-workers reported that oral administration of zerumbone caused suppression of dextran sodium sulfate-induced acute

Conclusion

In summary, this minireview clearly describes that zerumbone can affect multiple cell-signaling pathways involved in inflammation and cancer and thus has therapeutic potential against various inflammatory diseases and cancer. Both in vitro and in vivo data from published literature so far suggest that zerumbone can modulate multiple molecular targets that play pivotal role in both chronic inflammation and carcinogenesis. However, in future more detailed investigations are needed to completely

Conflict of interest

None.

Acknowledgments

This work was supported by grants from National Kidney Foundation [R-184-000-196-592] and Academic Research Fund [R-184-000-207-112] to GS. This work was also supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Ministry of Education, Science and Technology (MoEST) (No. 2011-0006220) to KSA. APK was supported by grants from the National Medical Research Council of Singapore [R-713-000-124-213] and Cancer Science Institute of Singapore, Experimental

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