Triclostatin A (TSA) also inhibits the action of histone deactylase (HDAC) and in this way inhibits the action of mediator vascular endothelial growth factor from the cancerous cells and prevents proliferation of tumour cells. The exact mechanism by which activity of HDAC is inhibited is not known clearly, but studies have demonstrated that a Zinc ion is chelated at the active pocket site of HDAC thus blocking catalytic reactions (Furumai 2001).
It also stimulates apoptosis action on cancerous cells and has an effect on angiogenesis (which is vital for tumour cell growth). In this way, there is strong evidence that TSA can be utilised as anticancer agents to help destroy cancerous growths (Williams 2001). TSA also activates O6-methylguanine-DNA methyltransferase (MGMT). The growth arrest of cancer cells mainly occurs at the G1 and the G2M phase (Enzo Life Sciences 2009). TSA when discovered initially was used as an antifungal agent, but with research studies it is becoming promising to utilise in cancer patients.
It has been extracted as a metabolite from the Streptomyces hygroscopicus organism. TSA modifies the TSA is also known to stimulate several genes that promote apoptosis and in this way the cancer cell may be removed from the body (Enzo Life Sciences 2009). TSA can also be utilised in combination with other substances such as TRAIL, increasing the apoptosis and causing greater effectiveness of the anticancer action. Certain cancerous cells that are resistant to TRAIL can effectively be sensitised to TRAIL by using TSA.
In a study conducted by Park Et al (2009) it was found that ovarian cancer cells were sensitised to TRAIL by TSA. TSA caused increased cytochrome accumulation in the cancerous cells and down-regulation of c-FLIP(L) through reduction of the EGFR pathway. The apoptosis action of TRAIL on the ovarian sensitised cells increased (Park 2009). In a study conducted by Jungel et al (2006), the action of TRAIL on TSA-sensitised rheumatoid arthritis synovial fibroblasts was determined.
When both drugs were administered together, the action was synergistic leading to increased apoptosis action of the fibroblasts. The exact mechanism by which this occurred is not known. The rheumatoid arthritis synovial fibroblasts contain DR5 or TRAILR2. However, even after treating with TSA, the DR5 did not decrease. TSA may up-regulate the levels of p21. This could be utilised as a novel treatment method for rheumatoid arthritis (Jungel 2006).
References
Campbell, D 2009, How Do You Treat Leukemia? , viewed 24 July 2009. http://www. montana. edu/wwwai/imsd/cancer/van1/vwtreatments. htm Enzo Life Sciences 2009, Trichostatin A, viewed 16 July 2009 http://www. enzolifesciences. com/Trichostatin_A. 211+M5ff5ac199ef. 0. html Furumai, R 2001, ‘Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin’, PNAS, vol. 98, no. 1, pp. 87-92. http://www. pnas. org/content/98/1/87. full. pdf