Characterisation of a novel bioactive complex polysaccharide from a marine invertebrate with potent anticancer and antimalarial activities

Khurshid, Chrow Ahmed 2017, Characterisation of a novel bioactive complex polysaccharide from a marine invertebrate with potent anticancer and antimalarial activities , PhD thesis, ELS.

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Considerable excitement has been generated by the discovery of active compounds from marine organisms. These compounds have a remarkable role in cancer treatment, with fewer side effects on general health. Sulphated glycosaminoglycan (GAGs) are present in all animals, vertebrate and invertebrate. They are of proven economic importance, not only in the food industry but also in the pharmaceutical field.

The present study identifies the key structural differences between the GAGs isolated from whelk and mammalian GAG and investigates their biological activity in relation to cancer and malaria. Glycans from marine sources are unique in terms of their structure and function. They work as an alternative natural source to provide effective treatment for several types of cancer, especially triple negative breast cancer (TNBC), which is the most aggressive type of cancer with fewer available treatment options. In addition, marine GAGs have a proven influence on malaria, although their mechanisms of action are not fully understood.

Several methods have been employed to achieve the aims of this study. The structure of whelk GAG was determined using several analytical techniques such as gel filtration chromatography, ion exchange chromatography, mass spectrometry and nuclei magnetic resonance spectroscopy. Enzymatic depolymerisation was also used to generate a library of fragments; each was then evaluated for its biological activity on cancer growth. Anti-proliferation activity on several cancer cells, including pulmonary adenocarcinoma A459, the MCF-7 ER-positive cell line, overexpression of protein HER2- SKBR3 cell line, the hepatoblastoma-derived cell line (Hep G2), chronic myelogenous leukaemia (K562), TNBC and mammosphere formation in breast cancer subtypes, and on malaria has been investigated in vitro using drug sustainable assays. Focusing on TNBC, the label-free quantitative proteomic approach has been used to gain overall insight into the mechanisms of action of whelk GAG on two TNBC cell lines: MDA-MB-468 and MDA-MB-231.

The results from whelk GAG analysis suggest a complex fine structure with a high sulphation levels that is clearly distinct from mammalian GAG. Few impurities were detected within the whelk GAG structure, which exhibits enzymatic resistance; this generated structurally indeterminate fragments. These resistant fragments still have significant biological activity against cancer growth. In vitro assays demonstrated significant inhibition activity of whelk GAG toward all types of cancer cells, mammosphere formation from breast cancer cells and malaria.

The mechanisms of action by which whelk GAG inhibits the growth of two TNBC cell lines appear to involve influencing the cell integrin signalling cascade, extracellular organisation pathways including the regulation of fibroblast growth factor FGF signalling and fibroblast growth factor receptors FGFR, cell adhesion and reduced glycolysis metabolism. In addition, whelk GAG affected the cell mitosis pathways by downregulating DNA replication proteins.

To our knowledge, this is the first study to identify significant structural differences between whelk GAGs and mammalian GAGs, which helps to explain the structural-functional relationship of marine glycans in inhibiting cancer cell growth. It also examines the biological role of GAGs isolated from whelk as anti-proliferation agents toward a wide variety of cancer cell lines and mammosphere formation in breast cancer. Finally, this study is the first to highlight the unique activity of whelk GAG against malaria infection.

Item Type: Thesis (PhD)
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Funders: University of Kirkuk - Ministry of Higher Education
Depositing User: Chrow Ahmed Khurshid
Date Deposited: 19 Feb 2018 12:50
Last Modified: 19 Feb 2018 12:50

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