Research review paperGold from the sea: Marine compounds as inhibitors of the hallmarks of cancer
Introduction
Despite considerable progress in medical research, cancer remains one of the high-ranking causes of death in the world. The National Cancer Institute estimates that “approximately 11.4 million Americans with a history of cancer were alive in January 2006. In 2010, about 569,490 Americans are expected to die of cancer, more than 1500 people a day. Cancer is the second most common cause of death in developed countries, exceeded only by heart disease. Cancer accounts for nearly 1 of every 4 deaths” (Source: Cancer Facts and Figs. 2010 of the American Cancer Society). Moreover, according to Lee Jong-Wook, former Director General of the WHO, “by the year 2020, cancer could kill more than 10.3 million people per year unless action is taken in both the field of prevention and treatment”.
Accordingly, research must continue to progress to improve existing therapies and to develop novel cures. For many years, research has essentially focused on plants and terrestrial microorganisms, mainly because these specimens are easily available and folk traditions have described beneficial effects from their use. However, recent pharmaceutical research is also focusing on marine organisms that have developed biologically unique molecules.
Life began in the sea, and oceans, particularly rich in biodiversity, cover over 70% of the Earth's surface. The lack of natural defenses (e.g. innate immune system) in the majority of invertebrates leads to the development of biologically active secondary metabolites, especially in marine and plant organisms like shells and spines. These metabolites play a role in the defense of the host habitats and the adaption to extreme environmental challenges. The variety of marine organisms discovered to date suggests a dramatic potential for drug discovery, and much remains to be discovered in the depths of the oceans.
Although the “silent world” has a much richer biodiversity than that of terrestrial areas, efforts to exploit this biodiversity through the identification of new chemical compounds have only begun: approximately 22,000 natural products of marine origin have been discovered so far, whereas 131,000 terrestrial natural products exist (Blunt et al., 2011).
The sea covers over 70% of the earth's surface and some areas, such as coral reefs, possess a huge biodiversity, which is even greater than that of rainforests. A large proportion of the sea offers untapped sources of potential drugs with promising activities due to a large diversity of marine habitats and environmental conditions (nutrient availability, sunlight presence, and salinity levels) (Scheuer, 1990). In the area of marine research, a recent census of marine life that involved the participation of 2700 scientists from over 80 nations assessed the diversity, distribution and abundance of marine life resulted in the discovery of over 6000 potentially novel species (Butler et al., 2010, Census of marine life Fautin et al., 2010, Miloslavich et al., 2010). As a consequence of these research efforts, it is clear that the marine environment represents an important source of unknown natural compounds whose medicinal potential must be evaluated.
Recent studies in the field of cancer research have revealed promising compounds, isolated from natural sources, with proven anticancer activity. Three examples are trabectedin, cytarabine and eribulin mesylate (Yondelis®; PharmaMar); (Cytosar-U®, Bedford, Enzon) (Halaven®; Eisai Inc.) (D'Incalci and Galmarini, 2010, Gradishar, 2011, O'Dwyer and Maslak, 2008), which represent the first three described marine anticancer drugs. Indeed, almost 50% of the antitumor agents approved in the last 50 years of the 20th century were either compounds derived from natural sources or (semi-) synthetic analogs of these products (Newman and Cragg, 2007). Natural compounds remain a high-output source of promising chemotherapeutic or chemopreventive agents in current cancer research (Dumontet and Jordan, 2010, Gullett et al., 2010, Villa and Gerwick, 2010). In addition to PharmaMar, other pharmaceutical companies including Bedford, Enzon, Eisai Inc., Novartis, Aventis, Eli Lilly, Abbott Inflazyme, Pfizer and Taiho Pharmaceuticals Co., have therapeutic compounds of marine origin under development.
It is well known that genetic changes progressively convert normal cells into cancer cells (Nowell, 1976). Although more than 100 distinct types of cancer exist, only six essential alterations in cell physiology cause malignant cell growth: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis and metastasis. Hanahan and Weinberg reported that these six “hallmarks of cancer” are present in almost every type of human tumor (Hanahan and Weinberg, 2000).
Although a large number of reviews on marine natural compounds exist (Blunt et al., 2010, Ebada et al., 2010, Lin et al., 2010, Penesyan et al., 2010, Villa and Gerwick, 2010), in this review, we focus on selected compounds and demonstrate how they interfere with these six crucial biological pathways described by Hanahan and Weinberg.
Section snippets
Compounds that abolish self-sufficiency in growth signals
Published data indicate that marine compounds exert chemopreventive and chemotherapeutic effects through the inhibition of phosphorylation of membrane receptors, including epidermal growth factor receptor (EGFR), as well as downstream cell signaling cascades. Some marine compounds efficiently interrupt constitutive growth factor stimulated cell signaling pathways, typically triggering a pathway involving Ras → Raf → extracellular regulated kinase (ERK) → mitogen-activated kinase/ERK-kinase (MEK) →
Conclusion
This review has presented a survey of different marine compounds acting on the six hallmarks of cancer. Interestingly, most of the natural compounds reported in this review lead to apoptosis induction in cancer cells, thus eliminating the source of the disease. This programmed cell death is targeted by most of the marine-derived anticancer drugs reported in this review, as shown in Table 2. Hence, it has to be pointed out that only the sixth hallmark reported by Hanahan and Weinberg (prevention
Acknowledgements
Research in MD's lab is supported by the “Recherche Cancer et Sang” foundation, the “Recherches Scientifiques Luxembourg” association, the “Een Häerz firkriibskrank Kanner” association, the Action Lions “Vaincre le Cancer” association and by Télévie Luxembourg. MK is supported by an AFR postdoctoral fellowship from the Fonds National de la Recherche Luxembourg. Editing and publication costs are covered by the Fonds National de la Recherche Luxembourg.
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