Inhibition of telomerase activity and cell growth by natural plant products in human brain cancer cells

Abstract

According to Global Cancer Statistics 2002, brain cancer, one of the most challenging cancers to treat, with its high mortality rate, accounted for 189,000 new cases and 142,000 deaths worldwide annually. Cancer Statistics 2005 reported 18,500 new cases and 12,760 deaths in the United States. Current therapies for brain cancer treatment include chemotherapy, radiotherapy and surgical removal. However, such treatments were reported to have limitations and complications that result in poor prognosis; difficulty in surgical removal, low long-term survival rate and side effects from chemotherapy and radiotherapy confound the efficacy of brain cancer therapy. Growing evidences point to the potential of phytochemicals such as plumbagin, genistein and curcumin as anti-cancer agents. However, the molecular mechanism(s) of action of these phytochemicals remain to be elucidated. Thus, by utilizing a variety of molecular and cytogenetic techniques, this study aims to investigate the potential of these phytochemicals with special attention paid to its possible role in the inhibition of telomerase and other oncogenic pathways in brain cancer cells. In the present study, we show dose-dependent decrease in cell viability following plumbagin and curcumin treatments accompanied by increased DNA damage which correlates to cell cycle arrest and cell death. Furthermore, treatment of cancer cells with these phytochemicals were shown to result in differential expression of genes and proteins related to cell cycle and cell death such as PTEN, E2F1, CCNE1, CDK2, Bcl2 and Survivin. Interestingly, genistein induced cell cycle arrest at G2/M phase without causing DNA damage and cell death. This cytostatic characteristic is a proposition for the use of genistein in combinatorial treatment to arrest or sensitize cancer cells to secondary cytotoxic drugs. We also found that radiosensitive cells have a higher tendency to undergo cell cycle arrest and cell death whereas radioresistant cells showed otherwise. In addition, all three drugs were shown to inhibit telomerase activity in brain cancer cells, resulting in shortening of telomere length following long-term treatment. To date, this property of plumbagin is the first to be reported in our study. The understanding of the molecular and genetic mechanisms involved in cancer resistance will be helpful in the development and validation of novel therapeutic agents in the treatment of human malignancies. As telomerase is expressed in 90 % of human tumours, telomerase inhibition is an attractive target for anticancer therapy. We propose that the above drugs may elicit anticancer effects via gene regulation and telomerase inhibition.