Bcl-2 Family Proteins in Development and Treatment of Malignant Diseases

Proteins of Bcl-2 family are key regulators of mitochondrial pathway of apoptosis. Deregulation of apoptosis disrupts the complex and delicate balance between cell proliferation, survival and death and plays an important role in the development of malignant diseases. In addition to uncontrolled proliferation, alterations in apoptotic proteins are frequently associated with resistance of malignant cells to chemotherapy, leading to ineffective treatment with chemotherapy that primarily acts by apoptosis initiation. Despite the progress in combinatory and biologic therapy, response rates for treatment of different malignant diseases are not high enough. Therefore, new anti-cancer agents that selectively kill tumour cells and spare normal tissues are still urgently needed. Progress in biochemistry and cell biology leading to detailed dissection of cell signalling pathways allows development of new therapeutic strategies targeting different proteins involved in malignant transformation and uncontrolled proliferation of malignant cells. Emerging knowledge on molecular mechanisms of apoptosis deregulation in cancer development has revealed Bcl-2 family proteins as potential targets for drugs discovery. Structural analysis of these proteins together with studies of apoptosis mechanisms have outlined strategies for generation of new drugs, resulting in numerous novel chemical entities with mechanism-based activity. Many of the most logical targets for promoting apoptosis of malignant cells are technically challenging, involving often disruption of protein interactions or changes in gene expression, as opposed to traditional pharmaceutical approach that predominantly attacks enzymes. Understanding of the core components of the apoptotic machinery at the molecular and structural levels may lead to new era in cancer therapy where the intrinsic and acquired resistance of malignant cells to apoptosis can be pharmacologically reversed, reinstating natural pathways of cell suicide.