Anticancer activities of oxidant-redox drug combinations in lipid excipients

Abstract

Genetic alterations in the redox status of cancer cells promotes a continuous and elevated production of reactive oxygen species (ROS), associated in the initiation and progression of tumours. The body's potent antioxidant system effectively neutralises ROS produced in normal cells, however, owing to high metabolic rates of cancer cells, ROS is generated at levels beyond the capacity of this antioxidant system. Many cancers are characterised by poor prognosis and high mortality, despite extensive research and substantial efforts for developing targeted cancer chemotherapeutics. Skin cancer represents the most frequent occurring cancers and melanoma, the leading cause of skin cancer related deaths. Breakthroughs in chemotherapeutics have been achieved in certain cancers, though marginal advances have been made in treatments for other malignancies such as metastatic melanoma. Strategies aimed at altering redox dysregulation in the presence of ROS inducers, present a promising new approach to cancer chemotherapeutics. This can be achieved by elevating oxidative stress beyond the toxicity threshold of cancer cells, sparing normal cells. This study considered the increasing incidence of skin cancer and the challenges of current therapeutic strategies. An alternative treatment strategy was proposed and investigated. Combination therapy of artemisone, elesclomol and lipid excipients; oleic acid, stearic acid and cholesterol is investigated, for the first time, for potential anticancer activity against A375 human melanoma cells. This study forms part of initial screenings for a larger project, "Rational development of combinations of known and novel drugs for chemotherapy of cancer", wherein rational oxidant and redox drug combinations are developed to target hypoxic and proliferating cancer cells. This approach relies on the susceptibility of cancer cells to oxidative stress. The in vitro cytotoxicity of the proposed combinations against A375 melanoma cells was assessed relative to cell viability, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and intracellular ROS accumulation, using the 2',7'- Dichlorofluorescein-diacetate (DCFH-DA) assay. The main findings in this study showed, for the first time, enhanced anticancer activity of artemisone and Cu(ll)-elesclomol when combined with lipid excipients, oleic acid, stearic acid and cholesterol. Combinations caused a dose dependant decrease in cell number and increase in ROS generation. Taken together, redox directed combinations with lipid excipients, should be thought of as potential alternative to traditional therapies and warrants further investigation.