Semenye, Petra (2025) Enteric Neuroprotection as a Therapeutic Strategy to Prevent Gastrointestinal Side Effects of Chemotherapy. Research Master thesis, Victoria University.

Abstract

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Although the impact of CRC can be significantly reduced through primary prevention strategies—such as adopting a healthy lifestyle, limiting alcohol consumption, and practicing early detection through screening—approximately 60% of CRC patients are diagnosed at or beyond stage III due to its aggressive and often asymptomatic nature in its early stages. At advanced stages of the disease, systemic treatment becomes the primary approach. Chemotherapy, particularly combination chemotherapy, is often used as the first-line treatment for metastatic CRC. These treatments aim to kill cancer cells and slow tumour growth. Oxaliplatin (OXL) is one of the primary chemotherapeutic agents used in CRC treatment, showing significant potential in enhancing tumour regression and improving patient survival. Despite its established success, OXL is associated with chronic neurological and gastrointestinal (GI) toxicities, which can limit its effectiveness and, in severe cases, lead to the cessation of treatment. These side effects present a major therapeutic challenge, underscoring the need for novel targets and therapies. High Mobility Group Box 1 (HMGB1) is a conserved nuclear protein involved in chromatin organization, transcription, and DNA repair. In response to stimuli such as chemotherapy, HMGB1 translocates to the extracellular matrix (ECM), where it acts as a damage-associated molecular pattern (DAMP). This translocation dysregulates signalling pathways involved in inflammation, immunity, angiogenesis, proliferation, metastasis, metabolism, apoptosis, and autophagy. Targeting HMGB1 may thus represent a promising therapeutic strategy for cancer and inflammatory-related diseases. Glycyrrhizin (GL) is an HMGB1 inhibitor with known therapeutic properties, including anti-inflammatory, anti-tumour, anti-viral, and neuroprotective effects. By mitigating HMGB1 overexpression and its translocation in cancer cells, GL has shown promise in enhancing the effectiveness of anticancer therapies. This thesis aims to investigate the effects of OXL administration on the enteric nervous system (ENS) and GI function, and to examine the neuroprotective and anticancer efficacy of GL when used in combination with OXL. Clinical parameters, such as body weight, survival, and tumour metastasis, were assessed. In vitro experiments were conducted to explore the morphological, immunological, and molecular mechanisms underlying these effects. The results demonstrated that OXL treatment alone caused significant neuronal loss in the myenteric plexus of the distal colon, which was associated with GI dysfunction due to altered gut mucosa integrity and inflammation. The study revealed that the mechanism underlying OXL-induced enteric neuropathy was primarily linked to oxidative stress in the myenteric plexus, as evidenced by increased cytoplasmic translocation of HMGB1 in mice treated with OXL. Co-treatment with GL alleviated oxidative stress, enhanced enteric neuronal survival, and improved GI function, while also exhibiting potent anti-tumour properties that reduced tumour burden and metastasis. This thesis establishes that enteric neuropathy resulting from oxidative stress and/or inflammation following OXL administration plays a significant role in GI dysfunction. Co-administration of GL with OXL alleviated enteric neuropathy, GI inflammation, and GI dysfunction. Therefore, the present work provides preliminary evidence for the potential use of GL as a therapy to mitigate chemotherapy-induced enteric neuropathy and GI dysfunction, due to its potent neuroprotective effects and ability to improve GI function.

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