Insights into the mechanism of drug action of a novel silver(I) chemotherapeutic against a malignant melanoma cell line

MSc. (Biochemistry)GLOBOCAN 2008 Survey reported that 12.7 million cancer cases with 7.6 million cancer deaths occurred with an astonishing 56% of these cases and 64% of these deaths allocated to economically developing countries, such as South Africa. Statistics are alarming concerning cutaneous malignant melanomas (CMM) with the World Health Organisation (WHO) estimating that 132 000 new cases of CMM arise per annum internationally with CMM incidence rates showing an increase of 28% in men and 12% increase in women worldwide; whilst the Cancer Association of South Africa (CANSA) has reported that skin cancer is the most common cancer in South Africa, with an estimated 20 000 new cases being reported per annum. Normal cells progressively transform into malignant tumours by a process that requires sequential acquisition of mutations in a genome damaged by various intrinsic and exogenous incidences resulting in two distinct and functional outcomes: 1) activation and/or expression of unfavourable oncogenes and 2) inactivation of tumour suppressor genes that code for proteins involved in checkpoints to cell proliferation or cell death. Transformation of dendritic melanocytic epidermal skin cells give rise to different types of skin cancers with CMM being predominant with poor prognosis and 90% of all deaths associated with cutaneous type tumours and CMM has been classified as a multifactorial disease where both environmental and genetic factors/mutations interact in concert to contribute to CMM susceptibility. Conceptual progress in the last decade has added two emerging hallmarks showing increased potential in generality to the already six known hallmarks of cancer, namely reprogramming of cellular energy metabolism and evasion of immune destruction by T and B lymphocytes and macrophages, enabled by core hallmark cancer characteristics such as genome instability and tumour-promoting inflammation. The Warburg Effect has been described, in terms of metabolic particularities of cancers, as an increased glucose uptake, via a shift in energy production from oxidative phosphorylation to a glycolytic pathway, with increased extracellular lactate release by tumours resulting in a consequent decrease in pH in the surrounding tissues, even in the presence of oxygen. This effect contributes to proliferation, invasiveness, metastasis and angiogenesis of malignant cells. Thus, chronic and uncontrolled cell proliferation, representing the essence of tumour growth, involves not only deregulatory control of cell proliferation but also a parallel adjustment to energy metabolic pathways in order to fuel cell growth and division. Over the last twenty years, studies have shown that the concept of programmed cell death (PCD), by apoptosis, serves as a natural barrier to cancer development where both the intrinsic and extrinsic apoptotic circuits conclude in the implementation of progressively..