Denspm ile paklıtaksel'ın uyardığı apoptotik hücre ölümünde poliamin metabolizması rolünün MCF-7 WT ve BCL-2+ hücrelerinde gösterilmesi

Abstract

Breast cancer, the most common cancer type all around the world and also in our country, is treated by surgery, radiotherapy, hormonal and chemotherapy. New combined drug treatments and their molecular machinery are become an important to overcome the drug resistance which was known to be major handicap during breast cancer treatments. Paclitaxel, a taxol derived chemotherapeutic agent, is used in various cancer types and metastatic breast cancer cases. Polyamines (PAs), are amine-derived polycations, are known to take role in cell division, differentiation and malignant proliferation. DENSpm, a PAs analogue, was determined to arrest cell cycle and induced apoptotic cell death via PA depletion in various cancer cells such as colon, melanoma, prostate and breast cancer cells. In this thesis, our aim is to investigate the role of polyamine metabolism in DENSpm and Paclitaxel induced apoptotic-autophagy cell death mechanism in MCF-7 wt and Bcl-2+ breast cancer cells. We determined that DENSpm and paclitaxel combined treatment decreases cell viability, induced apoptotic cell death by caspase activation and PARP cleavage in time-dependent manner in MCF-7 breast cancer cells. However, drug induced apoptotic cell death was observed following 48 hour drug treatment in MCF-7 Bcl2 overexpressed breast cancer cells. Moreover, we establihed that resistant profile against drugs might induced by autophagy regulation in breast cancer cells. DENSpm induced apoptotic cell death in MCF-7 cells by depletion of PA levels due to PA catabolic enzymes activation was also determined. In addition, PA catabolic enzyme; SSAT overexpression by plasmid transfection was demonstrated to overcome the drug induced resistant profile in breast cancer cells.