Date

2017

Author

Gök, Seher

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Although the traditional chemotherapeutic agents able to suppress breast tumor progression, they are mostly unspecific in their mechanism of action and have toxic effects to normal tissues. Instead, it has been reported that tumor cells are more sensitive to some forms of Vitamin E (VE) and its synthetic derivatives than healthy cells. Studies of drug-cell interactions and understanding the mechanism underlying cytotoxic activity and biological effects at molecular level in cancer model cells are essential in the preclinical stage of drug discovery. TC6OH, a derivative of α-tocopherol with side chain modification has be en shown to possess anti-cancer activity in preliminary studies. It was hypothesized that, as VE and VE analogs are fat soluble lipophilic molecules, they exert their function by modulating the lipid metabolism and related pathways. This study aimed to evaluate cellular impact of VE analog, using α-tocopherol as a reference compound through the experiments. Their effects on the cellular metabolism, biophysical properties of cellular lipids and functional characteristics of cells were monitored in human Estrogen Receptor (ER) positive breast cancer MCF7 cell line at 48 h drug exposure. Analog induces cell cycle arrest and differentiation, triggers apoptosis and inhibits migration while showing no cytotoxic effect on MCF10A breast epithelial cells at the same doses. In addition, analog treatment increases cellular fatty acid and cholesterol levels, changes the membrane dynamics while decreasing the lipid peroxidation which are thought to be related in apoptotic processes. It has been documented that analog treatment induces tumor cell apoptosis by dissipating mitochondrial membrane potential, modulating the lipid synthesis, transportation and degradation as well as down-regulating the certain anti-apoptotic and growth factor related proteins in MCF7 cells. Due to resistance of ER positive cells to the established therapies, the findings of this study are of translational value.  

Subject Keywords

Lipids., Vitamin E., Breast

URI

http://etd.lib.metu.edu.tr/upload/12621061/index.pdf
https://hdl.handle.net/11511/26451

Collections

Graduate School of Natural and Applied Sciences, Thesis