Show simple item record

dc.contributor.advisorZhou, Yaoqi
dc.contributor.advisorZhan, Jian
dc.contributor.authorAhmad, Haroon
dc.date.accessioned2019-12-06T02:08:18Z
dc.date.available2019-12-06T02:08:18Z
dc.date.issued2019
dc.identifier.doi10.25904/1912/2515
dc.identifier.urihttp://hdl.handle.net/10072/389574
dc.description.abstractCancer is a leading cause of deaths in the world. Cytotoxic drugs, target-specific drugs and peptide drugs are major types of the anticancer drugs. Cisplatin, a cytotoxic anticancer drug, is the most common platinum-based chemotherapeutic drug used in clinics. However, this drug has fatal side effects because of its nonspecific toxicity. In this thesis I report the development of platinum (IV) prodrugs conjugated with cancercell-specific peptides and demonstrated its specificity, cytotoxicity and apoptotic effects towards their respective target cancer cell lines. I further showed that similar to cisplatin (platinum (II) drug), the cell-specific cytotoxic mechanism of the new compounds is crosslinking of DNA. In addition to using peptide-conjugated small molecules for improving specificity, I developed peptide-based, anti-angiogenesis inhibitors for targeted therapy. Angiogenesis plays a key role in cancer growth, survival and metastasis. Clinically it has been shown that employing anti-angiogenesis inhibitors in combinational therapy with traditionally chemotherapeutic agents produce significantly better results. Human methionine aminopeptidase 2 (hMetAP2) removes N-terminal methionine (the start codon) from nascent allowing them to interact with the α subunit of eukaryotic initiation factor 2. It plays an active role in protein synthesis, cell proliferation, and angiogenesis. Thus, hMetAP2 has been an attractive drug target not only for cancers but also for chronic disorders such as agerelated macular degeneration, rheumatoid arthritis, obesity, and type-2 diabetes. Using computational tools, I designed a self-derived structural disrupting peptide drug targeting hMetAP2. In this thesis I show that this peptide can specifically inhibit the activity of hMetAP2 but not those of other human methionine aminopeptidases (hMetAP1 or hMetAP1D) in extracts of breast carcinoma cells (MCF7 and SKBR3). The liposome-delivered peptide inhibits hMetAP2 by changing its conformational state according to semi-native pulsed field gel electrophoresis (PAGE) and causes cell cycle arrest. The peptide delivered by either liposome or a cell-penetration peptide can inhibit cell proliferation, migration, and wound healing of both breast (MCF7) and colon (SW48, SW480) cancer cells with a lesser effect on non-neoplastic colon epithelial cells (FHC). Thus, the self-derived peptide from hMetAP2 could be useful as a new anti-angiogenesis agent for targeting cell growth and associated disorders.
dc.languageEnglish
dc.language.isoen
dc.publisherGriffith University
dc.publisher.placeBrisbane
dc.subject.keywordsAnticancer
dc.subject.keywordsTherapeutics
dc.subject.keywordshMetAP2
dc.subject.keywordsHuman methionine aminopeptidase 2
dc.titleDeveloping Peptide-Based Anticancer Therapeutics by Targeting Human Methionine Aminopeptidase-2 and Delivering Cisplatin in a Cell Type-Specific Manner
dc.typeGriffith thesis
gro.facultyGriffith Health
gro.rights.copyrightThe author owns the copyright in this thesis, unless stated otherwise.
gro.hasfulltextFull Text
gro.thesis.degreelevelThesis (PhD Doctorate)
gro.thesis.degreeprogramDoctor of Philosophy (PhD)
gro.departmentInstitute for Glycomics
gro.griffith.authorAhmad, Haroon


Files in this item

This item appears in the following Collection(s)

Show simple item record