Abstract
M.Sc.
Breast cancer is the most commonly diagnosed cancer and cause of death in women world wide as well as in South Africa. Cancer is characterized by over-proliferation of cells or the inhibition of programmed cell death known as apoptosis, a well coordinated process that results in the activation of several proteases and other hydrolytic enzymes. Apoptosis is regulated by enhancers and inhibitors, such as heat shock proteins (Hsps) that modulate the apoptotic process according to the demands of specific cells. Hsps can regulate the release of pro-apoptotic factors from the mitochondria as well as inhibit key steps in the apoptotic cascade such as activation of caspases. The Hsp70 family constitutes the most conserved and best studied class of Hsps and the stress-induced Hsp70 also blocks the apoptotic pathway at different levels. Hsp70 is furthermore overexpressed in several tumor cells and can effectively inhibit cell death induced by a wide range of stimuli including several cancer related stresses such as hyperthermia, chemotherapeutic agents and nonsteroidal anti-inflammatory drugs (NSAIDs) i.a. aspirin (acetylated salicylic acid) In addition to their potent analgesic, antipyretic and anti-inflammatory activity, NSAIDs can inhibit cell proliferation and induce apoptosis in many cancer cell lines. However, NSAIDs can also lower the temperature threshold for Hsp70 induction and induce a transcriptionally inert intermediate of Hsp70 that can be converted to a transcriptionally active state by a subsequent exposure to heat shock. This suggests that NSAIDs act differently under heat stress, possibly increasing cellular protection through the heat shock response in cancer cells with already elevated levels of Hsps. It is therefore hypothesized that the synergistic use of heat shock with salicylic acid (SA) treatment will increase Hsp70 expression and protein accumulation and further enhance the resistance of breast cancer cells to apoptosis.
The effects of SA on its own or in combination with HS on the viability of MCF-7 breast cancer cells as well as Hsp70 protein levels and gene expression were therefore investigated. SA treatments were found to induce cell death in a dose-dependent manner with the most significant decrease in viability observed after treatment with 20 mM SA.