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      Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

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          The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as “chemotaxonomic markers” for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk‐derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen‐containing compounds. The “promise” of a mollusk‐derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk‐derived anticancer agents and solutions to their procurement in quantity.

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          Global cancer statistics, 2012.

          Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests. © 2015 American Cancer Society.
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            Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

            In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with, number NCT00006353. Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
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              Tumor angiogenesis: therapeutic implications.

               J Folkman (1971)

                Author and article information

                Med Res Rev
                Med Res Rev
                Medicinal Research Reviews
                John Wiley and Sons Inc. (Hoboken )
                07 December 2016
                July 2017
                : 37
                : 4 ( doiID: 10.1002/med.2017.37.issue-4 )
                : 702-801
                [ 1 ] Consiglio Nazionale delle Ricerche (CNR)Istituto di Chimica Biomolecolare (ICB) Via Campi Flegrei 34 80078 PozzuoliItaly
                [ 2 ] Service de Neurochirurgie, Hôpital ErasmeUniversité Libre de Bruxelles (ULB) 1070 BrusselsBelgium
                [ 3 ] Department of Chemistry and BiochemistryTexas State University San Marcos TX 78666
                [ 4 ] Laboratoire de Cancérologie et de Toxicologie ExpérimentaleFaculté de Pharmacie, Université Libre de Bruxelles (ULB) 1050 BrusselsBelgium
                Author notes
                [* ] Correspondence to: Maria Letizia Ciavatta, Consiglio Nazionale delle Ricerche (CNR), Istituto di Chimica Biomolecolare (ICB), Via Campi Flegrei 34, 80078 Pozzuoli, Italy. E‐mail: lciavatta@ . Alexander Kornienko, Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium. E‐mail: a_k76@ . Robert Kiss, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666. E‐mail: rkiss2012@
                © 2016 The Authors Medicinal Research Reviews Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Figures: 29, Tables: 2, Pages: 100, Words: 45171
                Funded by: National Cancer Institute
                Award ID: CA186046‐01A1
                Funded by: Welch Foundation
                Award ID: AI‐0045
                Review Article
                Review Articles
                Custom metadata
                July 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.2 mode:remove_FC converted:26.06.2017


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