Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies

Abstract

Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

Keywords: apoptosis; cancer; defective apoptotic pathways; miRNAs; p53; small molecules.

Figure 1. Intrinsic and extrinsic apoptotic pathways

The intrinsic (mitochondrial) and the extrinsic (ligands/death receptors) cell death pathways and their convergence through t-Bid are depicted (see text for details)

Figure 2. Bcl-2 family members domain composition and function

Typical BH (Bcl-2 Homology) domains, listed from BH1 to BH4, are shown. TM: transmembrane domain.

Figure 3. Bcl-2 protein subgroups

The Bcl-2 proteins are classified into three subgroups, one group with anti-apoptotic and two with pro-apoptotic function, depending on the composition of the typical BH domains, listed from BH1 to BH4. Representative members of each subfamily are shown.

Figure 4. Function of inhibitors of apoptosis proteins (IAPs)

IAPs are often overexpressed in cancer and they have the ability to bind and inactivate caspases 9 and 3. The activities of IAPs, on the other hand, may be suppressed by mitochondrial proteins, such as Omi/HtrA2 and Smac/DIABLO, released into the cytosol during apoptosis.

Figure 5. Mechanisms leading to deregulation of apoptosis

Schematic representation of the different ways through which both the extrinsic and the intrinsic apoptotic pathways may be altered, resulting in reduction of apoptosis or acquisition of apoptosis resistance.

Figure 6. p53-mediated apoptosis

Role of p53 in both the extrinsic and the intrinsic pathway and their convergence through t-Bid.