From ancient herbs to modern drugs : In search of alternatives for cancer therapy

Abstract

Breast cancer is the major cause of deaths related to cancer for women worldwide. Although much is known about this malignancy, extensive research is still needed to gain complete understanding of the complexity of the disease. The inter and intra tumor heterogeneity is an important trait of breast cancer. The intratumor heterogeneity is reflected in sub-populations of cancer cells that appear to have different levels of aggressiveness. The most aggressive population termed the cancer stem cell (CSC) population is believed to play a critical role in cancer recurrence and resistance to conventional chemotherapy and CSCs seem to be the responsible for relapse and cancer death. Sesquiterpene lactones (SLs) and methoxyflavones, plant-derived molecules usually found in Asteraceae family plant extracts, have been reported to have anti-inflammatory and anti-cancer activities. This thesis describes the biological activity of natural and synthetized SLs and natural flavones on CSCs and non-CSCs in breast cancer cell lines.Damsin is a natural SL and it was used for the chemical synthesis of damsin derivatives. Here the toxicity of damsin and the damsin derivatives have been investigated in three breast cancer cell lines and one normal-like cell line. In all, 46 compounds were evaluated in dose-response testing to obtain IC50 values that were used to deduce structure activity relationships. Selected SLs were studied further to gain insight into cellular and molecular mechanisms. The studied SLs inhibited cell proliferation and cell migration and remarkably also reduced the CSC population of a breast cancer cell line. The damsin derivatives were more toxic to cancer cells than to normal cells. On the molecular level, the results point to interference of the function of the transcription factor NF-κΒ, being the molecular initiating event. SLs are known to bind to a cysteine in the DNA binding site of NF-κΒ. Our data implicate that it is not only DNA binding of NF-κΒ that is prevented by SL treatment but also the binding of other proteins that have a role in the function of NF-κΒ. The toxicity of three natural methoxyflavones was evaluated revealing that small differences in chemical structure can have a large impact on toxicity. Only one of the methoxyflavones showed anti-proliferative activity in breast cancer cell lines which may be caused by the induction of DNA strand breaks. In contrast to the SLs, treatment with the methoxyflavones did not reduce the CSC population