Overcoming the Dual Mechanism of Stress-Induced, Pgp-Mediated Drug Resistance using Novel Thiosemicarbazones

Abstract

Multi-drug resistance (MDR) is the principal mechanism by which many cancers develop resistance to chemotherapy drugs. It is the major factor responsible for the failure of many forms of chemotherapy. P-glycoprotein (Pgp) is the most highly studied ABC transporter involved in the efflux of cytotoxic substances out of the cell. Studies have shown that Pgp expression is up-regulated in tumour cells through the activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Interestingly, this protein is typically up-regulated by conditions of oxidative stress, such as hypoxia and nutrient limitation, and has been measured at elevated levels within tumours. Consequently, the tumour micro-environment may play an important part in regulating MDR. For the first time, the work reported in this thesis reveals underlying cellular pathways involving regulation of both surface and intracellular MDR by the tumour micro-environment. Moreover, the use of novel thiosemicarbazones to overcome MDR is demonstrated as a promising therapeutic strategy in combination with common chemotherapeutic agents that are subject to lysosomal trapping. These findings may help significantly improve the activity of existing chemotherapeutics and help improve patient treatment outcomes with potent thiosemicarbazones, such as Di-2-pyridylketone 4-cyclohexyl, 4-methyl-3-thiosemicarbazone (DpC), that will enter clinical trials in late 2015.