Lin X (2014) Discovery of antitumor agents with peptides from marine sources. JSM Clin Oncol Res 2(5): 1034.

The sea, covering 70% of the Earth’s surface, offers a considerably broader spectrum of biological diversity than terra firma. Containing approximately 75% of all living organisms, the marine environment offers a rich source of natural products with potential therapeutic applications. The discovery of the peptides from marine organisms as well as the understanding of the molecular mechanisms of action have contributed to developing peptides as promising lead drug candidates. Recently, marine peptides with biological properties have opened a new perspective for pharmaceutical developments. Many of the marine derived peptides show promising anticancer activity, and some of them have entered in human clinical trials for the treatment of cancer. Peptides discovered from marine organisms can induce cell death through different mechanisms, inducing apoptosis, affecting the tubulin-microtubule equilibrium, or inhibiting angiogenesis. The finding has increased our knowledge on understanding the relationship between the chemical structure of peptides and their biological activity.

In the past years, several peptides have been entered clinical trials and approved by FDA as anticancer agents. Aplidine (dehydrodidemnin B, Aplidin), a cyclic depsipeptide, was isolated from the Mediterranean tunicate Aplidium albicans. Aplidine can activate JNK pathway to induce cancer cell apoptosis.Aplidine also blocks the secretion of vascular endothelial growth factor (VEGF) and inhibits the corresponding VEGF-VEGF-Receptor-1 pathway in leukemic cells. Aplidin has entered into phase II clinical trials in Europe and Canada for the treatment of renal, head and neck, and medullary thyroid tumor. Dolastatin 10, a linear pentapeptide containing several unique amino acid subunits was derived from the marine mollusk Dolabella auricularia; it is the most potent member of a large class of related peptides. A synthetic dolastatin 10-based compound, monomethyl auristatin E (MMAE) showed very potent cytotoxicity to several human cancer cells. A conjugate, called Brentuximab vedotin (SGN-35, Adcetris) is designed, which consists of the anti-CD30 monoclonal antibody cAC10 conjugated with MMAE. SGN-35 has been approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of relapsed or refractory Hodgkin’s lymphoma (HL) and anaplastic large cell lymphoma. Since CD30 is highly expressed in some malignancies including HL and ALCL, the conjugate can target these kind cancer cells specifically.

Our laboratory also found several marine peptides with high anticancer activity. CS5931 is a novel linear polypeptide isolated from marine ascidian Ciona savignyi. CS5931 exhibited significant anti-proliferative and pro-apoptotic activities through the mitochondrial-mediated pathway. Caspase cleavage products, including cleaved caspase-9, caspases-3 and Cyt C were increased by CS5931. We also obtained a novel linear polypeptide from marine mollusk Meretrix meretrix, named mere15. Mere15 significantly suppressed the growth of human lung adenocarcinoma in a xenograft A549 nude mice model. Mere15 induced a dose-dependent release of Cyt C, the cleavage of procaspase-9, procaspase-3 and poly ADP-ribose polymerase (PARP). Treatment of the cancer cells A549 with this peptide resulted in a dose-dependent reduction of Bcl-2 levels, associated with a dose-dependent increase in the expression of Bax which was activated by p53 via a transcription-dependent mechanism. An antitumor protein, MML was also isolated in our laboratory from the coelomic fluid of Meretrix meretrix L., which exhibited significant cytotoxicity to several cancer cell types, including human hepatoma BEL-7402, breast cancer MCF-7 and colon cancer HCT-116 cells. Further studies demonstrated that MML increased cell membrane permeability and inhibited of tubulin polymerization. A polypeptide, called PG155, with potent antiangiogenic activity was isolated from the cartilage of shark, Prionace glauca. The effects of PG155 were evaluated using zebrafish embryos model in vivo. Our study confirmed that PG155 inhibited the growth of sub subintestinal vein (SIV) of zebra fish embryos. In vitro transwell experiments revealed that the polypeptide inhibited VEGF induced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs).

Peptide compounds are usually obtained from very different marine organisms and act through different mechanism of action. Compared with the peptides found from other sources, there is more diversity on the style/classes of marine peptides; more cyclic peptides or depsipeptide were found in marine organism. These marine peptides seem to be very useful and promising for biomedical research. There is no doubt that the diversity of marine peptides in its structure and mode of action provide a rich source off new potent and specific drugs with pharmaceutical applications in a wide variety of diseases.