Elsevier

Biotechnology Advances

Volume 29, Issue 5, September–October 2011, Pages 531-547
Biotechnology Advances

Research review paper
Gold from the sea: Marine compounds as inhibitors of the hallmarks of cancer

https://doi.org/10.1016/j.biotechadv.2011.02.002Get rights and content

Abstract

Cancer is one of the most deadly diseases in the world. Although advances in the field of chemo-preventive and therapeutic medicine have been made regularly over the last ten years, the search for novel anticancer treatments continues. In this field, the marine environment, with its rich variety of organisms, is a largely untapped source of novel compounds with potent antitumor activity. Although many reviews of marine anticancer compounds have been published, we focus here on selected marine compounds that act on the six hallmarks of cancer presented namely self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replication, sustained angiogenesis and tissue invasion and metastasis.

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.

References (169)

  • S. Grant et al.

    The use of cyclin-dependent kinase inhibitors alone or in combination with established cytotoxic drugs in cancer chemotherapy

    Drug Resist Updat

    (2003)
  • L. Guittat et al.

    Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro

    Biochim Biophys Acta

    (2005)
  • N.P. Gullett et al.

    Cancer prevention with natural compounds

    Semin Oncol

    (2010)
  • D. Hanahan et al.

    The hallmarks of cancer

    Cell

    (2000)
  • K. Hinterding et al.

    Synthesis and biological evaluation of aeroplysinin analogues: a new class of receptor tyrosine kinase inhibitors

    Bioorg Med Chem

    (1998)
  • S. Hiroishi et al.

    Antitumor effects of Marginisporum crassissimum (Rhodophyceae), a marine red alga

    Cancer Lett

    (2001)
  • Y. Huang et al.

    Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain

    Cell

    (2001)
  • M.F. Iademarco et al.

    Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1)

    J Biol Chem

    (1992)
  • K.A. Johnson et al.

    Drug development for cancer chemoprevention: focus on molecular targets

    Semin Oncol

    (2010)
  • R.J. Jones et al.

    Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro

    Blood

    (1990)
  • R. Kazlauskas et al.

    Heteronemin, a new scalarin type sesterterpene from the sponge image

    Tetrahedron Lett

    (1976)
  • M.A. Khanfar et al.

    Phenylmethylene hydantoins as prostate cancer invasion and migration inhibitors. CoMFA approach and QSAR analysis

    Eur J Med Chem

    (2010)
  • T. Klotz et al.

    Immunolocalization of inducible and constitutive nitric oxide synthases in human bladder cancer

    Urology

    (1999)
  • J. Kobayashi et al.

    Ageliferins, potent actomyosin ATPase activators from the Okinawan marine sponge Agelas sp

    Tetrahedron

    (1990)
  • D.V. Labarbera et al.

    Synthesis of imidazo[1,5,4-de]quinoxalin-9-ones, benzimidazole analogues of pyrroloiminoquinone marine natural products

    Bioorg Med Chem

    (2005)
  • J.F. Leal et al.

    Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines

    Biochem Pharmacol

    (2009)
  • N.Y. Lee et al.

    Inhibitory effects of fucoidan on activation of epidermal growth factor receptor and cell transformation in JB6 Cl41 cells

    Food Chem Toxicol

    (2008)
  • Y.H. Ling et al.

    Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models

    Eur J Cancer

    (2009)
  • M. Los et al.

    Apoptin, a tumor-selective killer

    Biochim Biophys Acta

    (2009)
  • M. Lu et al.

    XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization

    Mol Cell

    (2007)
  • S. Maddika et al.

    Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy

    Drug Resist Updat

    (2007)
  • A.M. Mayer et al.

    The odyssey of marine pharmaceuticals: a current pipeline perspective

    Trends Pharmacol Sci

    (2010)
  • J. Michels et al.

    Mcl-1

    Int J Biochem Cell Biol

    (2005)
  • C.P. Miller et al.

    NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells

    Blood

    (2007)
  • R.D. Ainnslie et al.

    Structure of malyngamide C

    J Org Chem

    (1985)
  • Y. Andersson et al.

    Downregulation of the antiapoptotic MCL-1 protein and apoptosis in MA-11 breast cancer cells induced by an anti-epidermal growth factor receptor-Pseudomonas exotoxin a immunotoxin

    Int J Cancer

    (2004)
  • P. Austin et al.

    Release of membrane-bound vesicles and inhibition of tumor cell adhesion by the peptide neopetrosiamide A

    PLoS ONE

    (2010)
  • R. Bai et al.

    Spongistatin 1, a highly cytotoxic, sponge-derived, marine natural product that inhibits mitosis, microtubule assembly, and the binding of vinblastine to tubulin

    Mol Pharmacol

    (1993)
  • J.W. Blunt et al.

    Marine natural products

    Nat Prod Rep

    (2010)
  • J.W. Blunt et al.

    Marine natural products

    Nat Prod Rep

    (2011)
  • A.J. Butler et al.

    Marine biodiversity in the Australian region

    PLoS ONE

    (2010)
  • A. Catassi et al.

    Characterization of apoptosis induced by marine natural products in non small cell lung cancer A549 cells

    Cell Mol Life Sci

    (2006)
  • Census of marine life
  • H. Chan et al.

    Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50–p65 recruitment

    Mol Cell Biol

    (1999)
  • J.H. Cho et al.

    Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules

    J Neurochem

    (2004)
  • Y.C. Chung et al.

    Significance of inflammatory cytokines in the progression of colorectal cancer

    Hepatogastroenterology

    (2003)
  • A. Cipres et al.

    Sceptrin, a marine natural compound, inhibits cell motility in a variety of cancer cell lines

    ACS Chem Biol

    (2010)
  • A. Ciucci et al.

    Induction of apoptosis in estrogen receptor-negative breast cancer cells by natural and synthetic cyclopentenones: role of the IkappaB kinase/nuclear factor-kappaB pathway

    Mol Pharmacol

    (2006)
  • E. Claudio et al.

    BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells

    Nat Immunol

    (2002)
  • F. Colotta et al.

    Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability

    Carcinogenesis

    (2009)
  • Cited by (121)

    View all citing articles on Scopus
    View full text