Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
| dc.contributor.advisor | Wong, W. L. (ABCT) | en_US |
| dc.contributor.advisor | Wong, K. Y. (ABCT) | en_US |
| dc.creator | Zheng, Boxin | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/14158 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Study the regulatory roles of human mitochondrial DNA G-quadruplex structures with target-specific fluorescent ligands | en_US |
| dcterms.abstract | Cancer is the second leading cause of death in humans, following cardiovascular and cerebrovascular diseases, and poses a critical threat in human health. Despite many new treatments have been proposed, the development of effective and safe cancer therapy remains a challenge. Mitochondria are known to take crucial roles in different biological processes, such as energy metabolism, proliferation and apoptosis, and they also have a close relationship with cancer development and progression. Thus, mitochondria are regarded as promising targets for cancer therapy. In recent years, many studies have shown that certain regions of human genes with guanine (G)-rich sequences may form a four-stranded structure containing two or more stacked G-tetrad planes of four guanines connected by a network of Hoogsteen hydrogen bonding, known as G-quadruplex structure (G4). It has been reported that tumor cells often overexpress G4s. Increasing evidence shows that G4s may play important roles in gene transcription and translation processes. In the mitochondrial genome, approximately 170 mitochondrial gene sequences are capable of forming G4s, which have been known closely associated with mitochondrial DNA deletions, energy metabolism, mitochondria-related diseases, and cancer progression. However, the regulatory function of mitochondrial DNA G-quadruplexes (G4-mtDNAs) is still unclear. This hinders the use of G4-mtDNA as a potential target for the development of new anticancer strategies. To understand the regulatory function of G4-mtDNAs, target-selective and cell-permeable small-molecule ligands are needed. Thus, the design and synthesis of small-molecule fluorescent ligands specifically targeting G4-mtDNAs in living cells is critical important. In this study, the primary objective is to design, synthesize, and isolate a series of G4-mtDNAs-targeting ligands and understand how these ligands could regulate the mitochondrial functions for anticancer therapy. In addition, the in vivo antitumor efficiency and biosafety of the potent and G4-mtDNA-targeting ligands screened are evaluated with human tumor xenograft mouse models. | en_US |
| dcterms.abstract | In the thesis, Chapter 1 summarizes the recent development of targeting G4-structures including G4-mtDNAs as the potential drug target of small molecules for anticancer study. An overview of research methods tailored for this study to achieve the objectives is given in Chapter 2. In Chapter 3 and Chapter 4, a comprehensive investigation of a small-sized benzoindole-benzothiazole ligand BYB, capable of targeting mitochondria and their G4-DNA structures, for antitumor study is discussed. The experimental results show that BYB is selectively targeting G4-mtDNAs, capable of stabilizing the structure of G4-mtDNAs upon interaction. BYB could also bind to G4-mtDNA targets to generate fluorescent signal for imaging and visualization in living human cancer cells. Moreover, BYB was found to be able to inhibit the proliferation of a panel of human cancer cells, including human cervical cancer cell HeLa. The anticancer mechanism of BYB targeting G4-mtDNAs was investigated in HeLa cells. The results suggest that BYB could inhibit the replication and transcription of mtDNAs, resulting in the downregulation of mitochondrial respiratory chain complexes. More importantly, the intracellular interaction of BYB with G4-mtDNAs could induce mitochondrial calcium overload in cancer cells. Calcium overload in mitochondria triggers a series of cellular events, including mitochondrial dysfunction, inhibition of ATP production, and elevated mtROS production, as well as the induction of mitophagy, ferroptosis, mtDNA and nuclear DNA damage, and apoptosis. To the best of our knowledge, this is the first study revealing that G4-mtDNA-targeting ligand induces mitochondrial calcium overload and then causes nuclear DNA damage and cell death. Moreover, the in vivo antitumor efficacy of BYB in a HeLa cell xenograft tumor model was validated. A 64.6% reduction in tumor weight was achieved with BYB in the in vivo study. | en_US |
| dcterms.abstract | The molecular design and synthesis of a series of small-sized di-cationic lipophilic ligands capable of targeting G4-mtDNAs and their anticancer mechanism are discussed in Chapter 5 and Chapter 6. To the best of our knowledge, this series of G4-mtDNA-targeting di-cationic ligands is first reported by us. Through different screening assays, ligand 9 is identified as a highly G4-mtDNA-selective ligand and exhibits potent antiproliferation activity against human colorectal cancer cell HCT116. The anticancer mechanism of the ligand was investigated in HCT116 cells. It was found that ligand 9 was specifically localized in mitochondria and significantly inhibited the expression of mitochondrial genes and then induced a series of cellular events, including mitochondrial dysfunction, ROS production, DNA damage, cellular senescence, and apoptosis. Furthermore, ligand 9 shows high antitumor efficacy in HCT116 tumor xenograft mouse model. A 70% reduction in tumor weight is achieved after the treatment with the ligand. | en_US |
| dcterms.abstract | Taken together, this study provides new insights into the design of G4-mtDNA-targeting ligands for chemical biology and new anticancer drug discovery. In addition, we revealed the possible antitumor mechanisms of targeting G4-mtDNAs with ligands. Particularly, the induction of mitochondrial calcium overload by G4-mtDNA-targeting ligands is reported for the first time. Due to targeting mitochondrial calcium signaling has the potential to reduce resistance induced by conventional chemical therapy, this new anticancer strategy targeting mitochondrial DNA G4s may provide a new opportunity to develop potent drug against drug-resistant cancers. | en_US |
| dcterms.extent | ix, 214 pages : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2025 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.LCSH | Mitochondrial DNA | en_US |
| dcterms.LCSH | Quadruplex nucleic acids | en_US |
| dcterms.LCSH | Antineoplastic agents | en_US |
| dcterms.LCSH | Hong Kong Polytechnic University -- Dissertations | en_US |
| dcterms.accessRights | open access | en_US |
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