Dr Catherine Kaschula – Investigations into the cancer preventative activity of dietary garlic in a murine colitis-associated cancer model
Dr Catherine Kaschula
- Lecturer, Department of Chemistry, University of Cape Town
Title of the project
Investigations into the cancer preventative activity of dietary garlic in a murine colitis-associated cancer model.
Cancer is a hyper-proliferative disease which results in over six million deaths per year. Most malignancies are diagnosed and treated at advanced stages with poor overall survival, thus cancer prevention is a key to managing the pandemic. Several lines of evidence suggest that 50-80% of cancers are preventable as their causation is largely exogenous with diet and lifestyle playing an important role . Garlic is a medicinal plant which has been used for centuries as both a flavour enhancer and for its beneficial health effects which include protection against cancer. This cancer preventative activity is ascribed to a group of sulfur-containing compounds which are found in crushed cloves of which ajoene is one of these compounds. These garlic compounds, including ajoene are reported to be active at inhibiting the three stages of tumourigenesis namely: initiation, promotion and progression (See Figure 1) and these effects are thought to be modulated on a chemical level through protein S-thiolation . In support, we have recently found that ajoene targets cancer promotion by inhibiting the proliferation and inducing apoptosis in growing cancer cells . In this study, ajoene was found to accumulate in the endoplasmic reticulum of MDA-MB-231 breast cancer cells where it was found to S-thiolate newly synthesized proteins and interfere with protein folding. In the presence of a cytotoxic concentration of ajoene, an accumulation of misfolded protein aggregates was found to trigger an ER stress response leading to apoptosis.
There is a list of proteins [5-8] which are susceptible to S-thiolation of specific cysteine sulfhydryl side chains by the tripeptide glutathione. This reaction is reversible and regarded as a post-translational modification commonly called S-glutathionylation  which is important in cell signalling. In our studies we have found that ajoene is able to S-thiolate numerous proteins in cancer cells, possibly in competition with GSSG. Indeed, based on the presence of a vinyl disulfide (as a better leaving group in the disulfide exchange), ajoene is expected to be the superior thiolating agent to GSSG. In fact, proteins that are susceptible to S-glutathionylation are probably the targets of ajoene. In support of this, the proteins identified to date to be S-thiolated by garlic allylsulfur compounds (tubulin, glutathione reductase and sulfurtransferases) are all proteins susceptible to S-glutathionylation. In the first part of this project we would like to synthesize an ajoene analogue bearing a biotin-functional group which can be used as a tool to isolate and identify those proteins from cancer cells which are the S-thiolation targets of ajoene. From the list of ajoene protein targets we would then like to generate a signalling map for ajoene in the cancer cell.
Apart from being effective at inhibiting cancer promotion, ajoene is also able to modulate the immune system favourably to counter tumorigenesis. We have recently found that ajoene is a natural non-steroidal anti-inflammatory (NSAID), able to inhibit Cox2 enzyme activity and to decrease expression of pro-inflammatory proteins in stimulated RAW293.7 macrophages (Kaschula unpublished).
Therefore, in the second part of the project we would like to evaluate whether regular dietary garlic intake can reduce the risk of cancer. Since epidemiological studies on garlic consumption and cancer risk are generally applicable to cancers of the digestive tract (stomach and colon) [9-11], we would like to study the effect of ajoene on a cancer of the distal colon whose formation is driven by inflammation.