Campelj, Dean G (2021) Unravelling the mechanisms of chemotherapy-induced cachexia and the potential of mitoprotective therapeutic strategies. PhD thesis, Victoria University.

Abstract

Chemotherapy is an effective first-line cancer-treatment to slow or even cure cancer. Despite it being widely used to treat a variety of cancers, the majority of agents used induce a myriad of serious sequalae. Recently, chemotherapy emerged as a key contributing factor to the induction of devastating wasting condition, cachexia. Cachexia involves the progressive loss of body mass, underscored by severe skeletal muscle wasting and dysfunction (skeletal myopathy). Unravelling the molecular mechanisms involved in the onset and persistence of chemotherapy-induced cachexia represents a complex scientific challenge and is of great clinical interest to identify novel drug targets and efficacious adjuvants. This thesis characterised the impact of individual chemotherapeutic agents on the skeletal muscular system of mice [doxorubicin (DOX) and irinotecan (IRI), 5-fluorouracil (5FU)] and evaluated the therapeutic efficacy of mitoprotective adjuvant candidates, sodium nitrate (with DOX) and BGP-15 (for 5FU and IRI) to protect body mass and skeletal muscle during chemotherapy. Additionally, since chemotherapeutic agents are usually administered to cancer patients in combination regimens which might escalate cachexia, we also characterised the impact of the ‘7+3’ (cytarabine and daunorubicin) chemotherapy induction regimen (CIR) utilised as standard treatment against acute myeloid leukemia. In this regard, we developed and characterised a novel murine model of AML CIR-induced cachexia. We also used this model to trace the course of cachexia during and after treatment and to evaluate whether voluntary exercise could be protective. The major findings of thesis were that the onset and severity of chemotherapy-induced cachexia is agent/regimen specific. While DOX, an anthracycline and topoisomerase-II inhibitor, and IRI, a topoisomerase- I inhibitor, induced a cachectic phenotype characterised by diminished body composition indices, and skeletal myopathy, 5FU, an anti-metabolite, did not cause cachexia. Interestingly, the multi-agent CIR induced severe cachexia. The recovery post-CIR was mixed with skeletal muscle mass returning to normal levels, while body and lean mass not completely recuperating in the 2-week recovery period. At the molecular level, the expression of key structural cytoskeletal proteins, i.e. dystrophin, were impacted by IRI and 5FU whether skeletal myopathy was observed or not. These data suggest that loss of dystrophin might be an early event in the myopathy associated with cachexia. With regard to the adjuvant candidates evaluated, sodium nitrate was not protective against DOX-induced cachexia, despite protecting against early signs of cardiomyopathy. BGP-15 displayed modest protection against IRI-induced cachexia but was not afforded the opportunity when evaluated in combination with 5FU. Alongside the CIR voluntary activity was not protective against cachexia, rather it potentiated CIR-induced cachexia, likely driven through enhanced loss of fat mass. Overall, these findings highlight that further investigation is required regarding the efficacy of mitoprotective adjuvant therapies against chemotherapy-induced cachexia.

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