Saudi Cultural Missions Theses & Dissertations
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Item Restricted MODULATION OF HYPOXIA INDUCIBLE FACTOR 1 ALPHA PLAYS A KEY ROLE IN THE TREATMENT OF HEPATOCELLULAR CARCINOMA AND ACCELERATES WOUND HEALING IN DIABETIC PATIENTS(Cleveland State University, 2024-07-21) Alghamdi, Uthman; Zhou, AiminHypoxia Inducible Factor 1 (HIF-1) is a heterodimeric transcriptional factor that plays a physiological role in low oxygen concentration or hypoxia. HIF-1 consists of two dimers: HIF-1alpha (HIF-1α) and HIF-1beta (HIF-1β). HIF-1 is the active oxygen-sensing domain in the cytoplasm that leads to stabilizing and overexpression of HIF-1 in the cells during hypoxia. On the other hand, HIF-1β is a stable domain in the nucleus that is required to form a dimer with HIF-1α in the DNA to express the HIF-1 gene. Upregulation of HIF-1α by either hypoxia or drug molecules has been elucidated to overexpress more than 100 tumor genes. These genes are involved in developing angiogenesis (vascularization), metastasizing, cellular proliferation, switching to anaerobic metabolism, and cellular survival. Hepatocellular carcinoma (HCC) is one of the solid tumors that have a hypoxic intratumor environment and relies on overexpression of HIF-1α to overcome hypoxia and allow cancer cells to survive, proliferate, and metastasize in these harsh conditions. Targeting or downregulating the HIF-1α gene in HCC with chemical compounds may provide a treatment for this cancer. However, inducing and overexpression of HIF-1α has many of benefits, such as accelerating wound healing in diabetic patients. Diabetic patients suffer from hyperglycemia and thick blood that delay wound healing and may cause infections. Upregulation of HIF-1α expression in diabetic wounds will increase the speed of the repair process of wound healing. HIF-1α plays a crucial role in all phases of wound healing by facilitating cell division, growth factor secretion, cell migration, survival in hypoxic environments, and matrix synthesis. We screened the LOPAC drug library to discover several chemical compounds that either inhibit or stimulate HIF-1α expression. These drug candidates have been further investigated to confirm their activity against HIF-1α expression. These findings suggest that up or downregulation of HIF-1α expression by these drugs has played a key role in treating HCC and accelerating the wound healing process.19 0Item Restricted Understanding the influence of radiotherapy in HCC cell lines, alone or when in combination with BCL-2 inhibitors(Saudi Digital Library, 2023-09-18) Alqarafi, Bashaer; Bird, Thomas; May, StephanieHepatocellular carcinoma (HCC) is the predominant form of liver cancer, accounting for approximately 90% of all cases. It is the third most common cause of cancer-related mortality worldwide. The development of this disease is associated with several risk factors, including liver inflammatory diseases, such as cirrhosis. Treatment options for advanced HCC are limited as the majority of patients present with incurable disease. Stereotactic ablative radiotherapy (SBRT) has recently been approved for patients who are not eligible for curative options. SBRT is reported to provide good tumour control, but patients often succumb to recurrent or metastatic disease. This could be due to a cancer's ability to evade cell death. Therefore, there is a significant opportunity for combining SBRT and systemic therapy to improve treatment outcomes. The intrinsic apoptosis pathway plays a crucial role in programmed cell death. Disruption of this pathway can lead to uncontrolled cell division. Therefore, there is untapped potential in combining SBRT with treatments that promote cell death (termed BH3-mimetics). The aims of this study were to: 1) assess the radiosensitivity of an HCC cell line (Hep53.4) using in vitro clonogenic assays; 2) evaluate the potential synergistic effect of combination SBRT and BH3-mimetic treatment (e.g. ABT263) using in vitro cell viability assays, and 3) examine whether SBRT causes radiation-induced liver disease in vivo in murine models using immunohistochemistry. Key findings of this study indicate that Hep53.4 cells are radiosensitive and combination treatment with 6Gy irradiation and ABT263, had a synergistic killing effect. Additionally, histological analysis of collagen markers revealed that SBRT effectively spares healthy liver tissue, whilst modifying the tumour collagen deposition compared to non-irradiated tumour controls. While in vitro data displays promising outcomes regarding the synergistic potential of systemic BH3-mimetic therapy and SBRT, further pre-clinical studies are imperative to establish its applicability in the clinical setting.25 0