Potential for modulation of cancer-associated oxidative stress : an in vitro investigation

[摘要] ENGLISH ABSTRACT: While cancer is a chronic, complex disease associated with a multitude of steps in its initiation and progression, all cancers generally have similar underlying maladaptive physiological mechanisms which may be addressed in order to prevent or treat this disease. Interest in the context of this thesis was in two of these maladaptive mechanisms, namely inflammation and oxidative stress. Both unresolved or severe inflammation and oxidative stress have been associated with cancer aetiology, and therefore administration of an anti-inflammatory or antioxidant could potentially prevent the initiation and progression of cancer. Current conventional cancer therapies are associated with a wide range of adverse side effects, leading to much interest in plant-based alternatives. For the purpose of this thesis, Δ-7 mesembrenone, a potent antioxidant isolated from Sceletium tortuosum and Cannabidiol, an antioxidant and anti-inflammatory extracted from Cannabis sativa, were studied in the context of breast cancer treatment.The potential anti-cancer activity of Δ-7 mesembrenone and Cannabidiol were investigated in three breast cell models in vitro. MCF12A, MCF7 and MDA-MB-231 cells were treated with varying doses of Δ-7 mesembrenone and Cannabidiol in isolation or in combination for a period of 24 hours, and the effects on cell viability and mitochondrial reductive capacity were assessed. Following this, the ROS production and the GSH/GSSG ratio were determined.Δ-7 mesembrenone in isolation resulted in cytotoxicity and increased ROS production across all cell models. Cannabidiol exposure in estrogen receptor positive breast cancer resulted in reductions in cell viability and mitochondrial reductive capacity, corresponding to an increased ROS production in these cells. No toxic effects of CBD were evident in the estrogen receptor negative breast cancer or normal breast cells at lower doses. Finally, combination treatments resulted in adverse effects across all cell models and at combined high doses, the negative effects were cumulative.We conclude that Δ-7 mesembrenone has no benefit in the context of breast cancer, as it exhibited significant levels of cytotoxicity in normal healthy breast cells at all concentrations reducing cancer cell survival, which could not be countered by Cannabidiol co-treatment. Cannabidiol showed more promise as an anti-cancer drug due to its high levels of cytotoxicity and the increased ROS production it induced in the estrogen receptor positive breast cancer cell line. Both the normal breast cells and the estrogen receptor negative cells exhibited little side effects than can be ascribed to Cannabidiol, illustrating the importance of this treatment in certain types of breast cancer only. Further research is warranted to better elucidate the cellular mechanisms involved and potential for treatment with this extract.

[发布机构] Stellenbosch University