Abstract
Dynamic protein-protein interactions between proapoptotic and pro-survival Bcl-2 family members regulate outer-mitochondrial membrane permeabilization and cytochrome c release, key events in the path to apoptosis. Their relative levels often dictate the fate of a cell following an apoptotic stimulus. However, in cancer cells, the pro-survival Bcl-2 family members are frequently upregulated, thereby creating a constitutive block to apoptosis and resulting in continued cell survival under conditions that normally result in cell death. Because many chemotherapeutics used to treat cancer also trigger apoptosis, this upregulation of pro-survival members also contributes to resistance to conventional cancer therapies. Strategies that inactivate pro-survival Bcl-2 family members therefore suggest a means by which this downstream block in apoptosis can be alleviated, resulting in the selective killing of malignant cells. Here, we outline the progress of three small-molecule Bcl-2 antagonists that have advanced into clinical evaluation.
Highlights
Dynamic protein–protein interactions between cancer cells manifest stress signals such as transformproapoptotic and pro-survival Bcl-2 family members ing oncogenes that trigger apoptosis and should result regulate outer-mitochondrial membrane permeabi- in their self-elimination and corresponding abrogation lization and cytochrome c release, key events in the in tumour formation 1
Because many chemotherapeutic a constitutive block to apoptosis and resulting in con- drugs used to treat cancer trigger apoptosis, evatinued cell survival under conditions that normally re- sion of apoptosis may contribute to the resistance sult in cell death
Strategies that inactivate pro-survival Bcl-2 family mem- Many apoptotic signals, such as DNA damage and bers suggest a means by which this oncogene activation, initiate signalling cascades that downstream block in apoptosis can be alleviated, re- converge on the permeabilization of the outer mitosulting in the selective killing of malignant cells
Summary
Destruction [2,3,4]. These pathways are both executed and regulated by the Bcl-2 family of proteins, which comprise three groups, defined according to function and Apoptosis evolved in metazoans as a means to main- to Bcl-2 homology (BH) domain content [5,6,7,8]: tain tissue homeostasis by eliminating unwanted or damaged cells. Bax and Bak are present as inactive monomers under normal conditions; following a death signal, they can undergo homo- and hetero-oligomerization within the OMM, causing OMM permeabilization and the egress of This third-party editorial was made possible through cytochrome c from the inter-membrane space. The last group, a large and diverse proapoptotic group within this family, contains only a single BH3 domain and includes Bim, Puma, Bid, Bad, Bik, Noxa, and others They respond to death signals upstream of Bax and Bak, resulting in their activation or upregulation (or both). The BH3-only proteins have been proposed to form two distinct groups: those that sensitize cells to apoptosis by binding to anti-apoptotic Bcl-2 proteins (Puma, Bad, Noxa, and Bik), and those that in addition directly activate proapoptotic Bax or Bak (Bim and Bid) 14,15. Strategies that target the functional BH3-binding groove of these pro-survival Bcl-2 family members in an attempt to reinstate an effective apoptosis pathway hold significant therapeutic promise in oncology [22,23]
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