Bishop, Maya Shakya (2022) Neuroprotective and Anti-Cancer Efficacy of APX3330 Given in Combination with Irinotecan and Oxaliplatin. Research Master thesis, Victoria University.

Abstract

Colorectal Cancer (CRC) is considered one of the most aggressive cancers and causes the second most cancer-related deaths in Australia. Chemotherapy is the standard first-line treatment for stage three or metastatic cancer. It is given as a combination of two or more chemotherapeutic drugs with other medications by themselves or with radiation. Oxaliplatin (OXL) and Irinotecan (IRI) are the most common chemotherapy medications used in the clinical setting for CRC treatment. Regardless of the success rate of reducing disease progression and increasing survival, these drugs cause acute and chronic toxicities that lead to immediate and long-term adverse effects. Most medications currently in clinical use to alleviate the gastrointestinal side-effects of anti-cancer chemotherapy cause adverse effects and, in many cases, are of limited efficacy; therefore, searching for novel targets and therapies is crucial. Apurinic/apyrimidinic endonuclease 1/ Reduction-oxidation factor-1 (APE1/Ref-1), is the recent therapeutic target that addresses both oxidative stress damage and DNA repair damage due to pathological condition of cancer. APE1/Ref-1 functions as a dual-functioning molecule containing a redox-active site and a DNA repair active site. The redox-active site of the protein mainly regulates cellular antioxidant response while the DNA repair active site is highly attuned to cell survival and preventing apoptosis. Therefore, we hypothesised that APE1/Ref-1’s capacity in regulating DNA repair pathway potentially leads to alleviating the damage to the enteric nervous system (ENS) that causes gastrointestinal (GI) dysfunction. APX3330, a small molecular inhibitor of APE1/Ref-1, was used in this study. A murine model with and without CRC was subjected 1) to investigate the efficacy of APX3330 treatment given in combination with IRI and OXL to alleviate neuronal toxicity associated with these chemotherapeutics, and 2) to assess the anti-tumour efficacy of combination treatment compared to treatment with individual chemotherapeutics. Assessment of body weights, faecal water content, and quantification of faecal lipocalin-2 were performed as a part of the evaluation of clinical parameters. Ex vivo experiments to study morphological, immunological, and molecular mechanistic parameters were also utilised to address those aims. This thesis aimed to identify novel therapeutic targets to alleviate ENS neuropathy due to the side-effects of Irinotecan and Oxaliplatin treatments and examine the neuroprotective and anti-tumour efficacy of APX3330 for CRC, which has not been explored yet. Based on our research findings, it is fair to conclude that the mechanisms underlying chemotherapy-induced gastrointestinal dysfunction arise because of complex and multifaceted mechanisms. Importantly, our research presented for the first time APX3330 showed enhanced enteric neuronal survival and improved GI function following Oxaliplatin and Irinotecan treatment. APX3330 treatment reduced the severity of constipation following Oxaliplatin treatment and alleviated Irinotecan-induced diarrhoea. Furthermore, results show that the impediment of the APE1/Ref-1 redox signalling pathway alleviated myenteric neuronal damage and it exhibited anti-tumour properties that aid in attenuating tumours and diminishing tumour metastasis. This thesis has demonstrated that individual administration of Oxaliplatin and Irinotecan caused neuronal damage and substantial reduction of myenteric neurons in the distal colon, significantly correlated with gastrointestinal dysfunction. While the effects of combination chemotherapeutic treatments on the enteric nervous system have yet to be further investigated, present work on using APX3330 combined with Oxaliplatin and Irinotecan to treat CRC successfully provides the groundwork for investigating consequent enteric neuronal survival and improved gastrointestinal dysfunction. Future research needs to be conducted to determine the molecular level interactions and possible regulatory pathways to better understand the subcellular interactions of the treatment agents and other proteins. Our research and previous findings show that pharmacologically protecting enteric neurons holds a robust future direction to alleviate chemotherapy-induced enteric neuropathy and gastrointestinal dysfunction.

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