Targeting of Bcl-2 family proteins for treatment of acute leukaemia

Abstract

Many studies suggest that killing of tumour cell by commonly used therapies (chemotherapy, radiotherapy) is mediated primarily by induction of apoptosis. Therefore, resistance of tumour cells to therapy can be caused by a failure in the ability to initiate apoptosis. Defects in apoptosis signalling pathways are also one of the main features of cancer, and particularly acute leukaemia. Malignant cells constantly resist the effects of cellular stress (e.g. DNA damage, oncogene activation), which would cause death of normal cells through apoptosis. Dysregulation of apoptosis has therefore give rise to tumour growth, disease progression and resistance of malignant cells to chemotherapy. Structural analysis of Bcl-2 family proteins playing a key role in regulation of mitochondrial apoptosis together with studies of their biochemical functions have outlines strategies for generation of drugs, resulting in numerous novel chemical entities with potential to reverse resistance of malignant cells to apoptosis. The use of these therapeutic approaches may in the future represent a new way in cancer therapy with high potential to improve clinical outcome and prognosis of acute leukaemia patients.