[Impact, and treatment possibility of chemotherapy resistance in cancer].

Abstract

Chemotherapy resistance in tumours is due to complex processes and is responsible for about half of all cancer deaths. In my thesis, I have investigated multiple different resistance mechanisms, most in depth the effect of multidrug resistance (MDR) caused by expression and function of P-glycoprotein (Pgp), and the MDR-selective compounds (such as NSC297366) effectively targeting it. The mechanism was investigated using cell models with different Pgp expression. Seeking the mechanism of action of the MDR-selective NSC297366, we showed that the intracellular iron-binding chelator molecule is able to reduce the amount of free iron available within the cell. Furthermore, by active efflux through Pgp in MDR cells, the compounds can lead to intracellular iron deficiency, upregulation of iron-demanding processes such as cell cycle and apoptosis, and selective death of MDR cancer cells. Our results raise the possibility of targeted killing of MDR phenotypic cancer cells resistant to other therapies, which in combination with conventional chemotherapeutic approaches may form the basis of a strategy of long-term control of the disease.