Active Targeted Therapy to Cancer Diseases Mediated by Lectins
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Universidade de Lisboa Faculdade de Farmácia Active targeted therapy to cancer diseases mediated by lectins Domingos João Baptista Pires Mestrado Integrado em Ciências Farmacêuticas 2017 Universidade de Lisboa Faculdade de Farmácia Active targeted therapy to cancer diseases mediated by lectins Domingos João Baptista Pires Monografia de Mestrado Integrado em Ciências Farmacêuticas apresentada à Universidade de Lisboa através da Faculdade de Farmácia Orientador: Prof. Dra. Ana Cristina Ferreira da Conceição Ribeiro 2017 2 Resumo As lectinas são proteínas com diversas funções biológicas existindo em todos os organismos vivos. Para cada organismo as lectinas endógenas exibem importantes funções na manutenção da homeostasia do organismo e na defesa frente a ameaças externas. As lectinas purificadas de outras fontes podem ser utilizadas de modo a exibirem as sua bioactividades em outros organismos. Uma das mais marcantes propriedades das lectinas é a sua afinidade para hidratos de carbono aberrantes presentes em proteínas e lípidos na superfície das células. As alterações sofridas por estes hidratos de carbono é uma característica associada ao processo de mutação celular presente no cancro que afecta o processo de diferenciação celular, um dos processos de modificação pós-tradução mais importantes a nível das proteínas da superfície celular. Esta especificidade associada à citotoxicidade descrita de diversas lectinas vegetais, permite que as lectinas vegetais induzam morte celular programa, levando ao desenvolvimento de estudos na área da terapêutica tumoral no sentido de utilizar as lectinas vegetais como agentes anticancerígenos com capacidade de actuar apenas em células malignas sem afectar células saudáveis. Assim, esta monografia foca-se essencialmente nas aplicações terapêuticas das lectinas de leguminosas no cancro, tentando antes contextualizar o que são lectinas, as suas aplicações e mecanismos de acção, assim como a sua relevância actual e potencial futuro. 3 Abstract Lectins are proteins that exist in all living organisms and possess a multitude of biological functions. In each organism endogenous lectins play a major role both in maintaining homeostasis and protection from external threats. Lectins purified from other sources can be utilized as exhibit they biological functions in different organisms from the one from which they were extracted. One of the most defining properties of lectins is their affinity towards aberrant carbohydrates expressed by cell surface proteins and lipids. This carbohydrate aberration is a hallmark associated with the malignant transformation of cells associated with cancer, which alters the cellular glycosylation process, one of the most important post- translational modification processes in cell surface proteins. This affinity, in conjuction with the citotoxicity associated with several legume lectins, reported to be able to induce programmed cell death by several different studies, lead to the development of studies in the tumour therapeutic field with the intention of utilizing legume lectins as anticancer agents with the ability to affect malignant cells without affecting healthy cells. This work focuses mainly in the therapeutic applications of legume lectins in cancer, providing beforehand context of what lectins are, their applications, how they exert their action and their current relevance as well as future potential. 4 Methodology This work was based on previously published documents, consisting of books and scientific articles. The survey was done using the pubmed database by keyword, selecting articles relating to the study in question. These articles, after consultation allowed to further extend the research. This research focuses on the characterization, biological activities and the role that lectins contemplate upon a specific recognition mechanism to carbohydrates, allowing their application in cancer as a therapeutic agent. The research focused on articles published in the last 20 years, including comments, as well as some older articles, which were part of history and that became important to contextualize. Key words: Legume lectin, Cancer therapy, Aberrant glycosylation 5 Content Resumo ......................................................................................................................................................... 3 Abstract ........................................................................................................................................................ 4 Methodology ................................................................................................................................................ 5 1. Introduction ......................................................................................................................................... 7 2. Distribution and Occurrence ..................................................................................................................... 8 3. Classification ............................................................................................................................................ 9 3.1. Plant lectins ....................................................................................................................................... 9 3.2. Animal Lectins ................................................................................................................................ 11 4. Plant Lectins Structural Features ............................................................................................................ 12 4.1. Legume lectin Monomer ................................................................................................................. 12 4.2. Quaternary structure ........................................................................................................................ 14 4.3. Carbohydrate binding site ............................................................................................................... 15 5. Functions and Bioactivity ....................................................................................................................... 18 5.1. Antifungal and Antibacterial Activity ............................................................................................. 18 5.2. Anti insect and Antiparasitic Activity ............................................................................................. 19 5.3. Antiviral Activity ............................................................................................................................ 20 5.4. Toxicity ........................................................................................................................................... 20 5.5. Anticancer activity .......................................................................................................................... 21 6. Aberrant glycosylation caused by malignant transformation ................................................................. 22 7. Anticancer activity mechanism .............................................................................................................. 25 7.1. Apoptosis ........................................................................................................................................ 25 7.1.1. Extrinsic pathway .................................................................................................................... 26 7.1.2. Intrinsic pathway ..................................................................................................................... 27 7.2. Autophagy ....................................................................................................................................... 27 8. Biomedical applications ......................................................................................................................... 30 8.1. Diagnostics ...................................................................................................................................... 31 8.2. Therapeutics .................................................................................................................................... 32 8.2.1. Direct antitumor activity .......................................................................................................... 32 8.2.2. Biological response modifier ................................................................................................... 33 8.2.3. Site Specific Drug Delivery Systems ....................................................................................... 33 8.2.3.1. Nanoparticle Systems………………………………………………………………………………………………..…..34 8.2.3.1 Immunotoxins……………………………………………………………………………………………..…………………37 9. Conclusions ............................................................................................................................................ 38 References .................................................................................................................................................. 39 6 1. Introduction With the improvement of healthcare through vaccination, antibiotics, improved sanitation and efforts to increase public awareness and promote better living and health habits there has been a noticeable decrease in infectious diseases during the last century. This increased control over the spreading of such diseases has diminished the threat that these diseases pose, as such cancer related diseases have overtaken