| Abstract: |
Apoptosis, or programmed cell death, is an essential process in development and tissue homeostasis. The biology is regulated by complex interactions between pro-apoptotic (i.e. pro-death) and anti-apoptotic (i.e. pro-survival) proteins. The delicate balance between these opposing forces dictates a cell's fate and plays a critical role in tumorigenesis. Alterations that lead to the deregulation of this balance in favor of cell survival can lead to the development of various human ailments, including cancer. Despite the frequent dysregulation of these pathways across all malignant diseases, the lymphomas stand out as the disease group where both biology and pharmacology blend, albeit not perfectly, to establish important proof-of-principal concepts. In this fascinating disease context, not only do alterations in these cell death pathways contribute directly to lymphomagenesis, but they can also render malignant cells resistant to conventional chemotherapeutic agents, serving as an escape mechanism over time. Over the past several decades, attempts to leverage our understanding of the dysregulation of cell death pathways have led to many novel cancer therapeutics, starting from the introduction of traditional non-specific chemotherapy agents to more recent agents that target very specific interactions among the cast of members governing the balance between pro-death and pro-survival. Members of the BCL2 family are the key components of the intrinsic mitochondrial apoptotic pathway and share sequence homology, known as BCL2 homology (BH) domains, which influence structure and function (Cory et al. 2003). As outlined in greater detail in the preceding chapter, BCL2 family members can be divided into two distinct groups: (i) anti-apoptotic proteins which include BCL2, BCL-XL, BCL-W, MCL-1, and A1/BFL-1; and (ii) pro-apoptotic proteins such as BAX, BAK, BOK, BIM, PUMA, BID, BIK, BAD, and NOXA. These two groups share certain BH domains, with pro-survival proteins sharing all four BH domains (BH1, BH2, BH3, and BH4), while pro-apoptotic proteins share only BH3 homology, specifically with BAX, BAK, and BOK sharing BH1-3, and BIK, BID, BAD, BIM, PUMA, and NOXA harboring only the BH3 domain, which is the basis for referring to these specific proteins as "BH3-only proteins" (Huang and Strasser 2000; Youle and Strasser 2008). Again, the balance between the two distinct functional groups influences the survival of a cell. While the biological mechanisms of the apoptotic pathway have been discussed in detail in preceding chapters, herein we will review the history and pharmacological features of drugs that induce apoptosis and possible biomarkers that can predict response to these agents. © 2023 John Wiley & Sons, Inc. All rights reserved. |
