Apoptosis Targeted Therapies

Apoptosis, or programmed cell death, in normal human tissues has an essential role in controlling overall cell number. In many human tumors apoptosis is impaired, contributing to cellular transformation. Triggering of apoptosis is determined by the ratio of pro- and antiapoptotic proteins, in particular, members of the Bcl2 family, the intracellular anti-apoptotic proteins (IAPs), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), and the caspase family. Although cytotoxic chemotherapy drugs can induce apopto-sis in malignant cells, resistance to chemotherapy may in some instances relate to alteration in the molecular pathways that regulate apoptosis.

There are two major apoptotic pathways that can be triggered in cells: the extrinsic death-receptor-induced extrinsic pathway, and the intrinsic mitochondrial apoptosome-medi-ated pathway (Figure 5.3). The extrinsic pathway is regulated by members of the TNF superfamily, FASL (FAS ligand), TNF, and TRAIL. These "death receptors" signal through the "death-inducing signaling complex" (DISC), leading to caspase activation and apoptosis. The intrinsic mitochondria apoptosome pathway is controlled by members of the Bcl2 family. The proapoptotic members of this family (e.g., BAX, BAK, BIM, and BID) precipitate the release of cytochrome c from mitochondria, which promotes the formation of the apoptosome (cytochrome c/APAF1/caspase 9) complex. Members of the Bcl2 family that inhibit the pathway include figure 5.3. Apoptosis-targeted therapies.

figure 5.3. Apoptosis-targeted therapies.

Bcl2 itself, Bclxl, and Bclw. P53 can regulate both the intrinsic pathway by promoting the transcription of BAX and the extrinsic pathway through upregulation of the death receptor. Apoptosis is also suppressed by the IAPs (inhibitors of apo-ptosis). Members of this family include XIAP, IAP1, IAP2, and survivin. These proteins interact with and inhibit selected effector caspases. IAP suppressors have also been identified and include Smac/DIABLO and XAF1.

Many of the targeted therapies mentioned above act in part through the promotion of apoptosis; for example, the pro-teosome inhibitor bortezomib and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) precipitate apoptosis in tumor cells. Similarly, flavopiridol-mediated inhibition of the cell-cycle kinase, cdkl, enhances the cytotoxicity of doxorubicin in MCF7 human breast carcinoma xenografts through the suppression of survivin phosphoryla-tion.81 However, some of the more direct therapies targeting components of the apoptosis pathway are discussed next.

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