Mechanisms of Deregulation of Apoptosis in Myeloma

Programmed cell death is a fundamental cellular program that is inherent in every cell of the human body. Apoptosis represents one of the most extensively studied forms of programmed cell death that plays a critical role during various physiological processes as well as in a variety of pathological conditions. Against the background that tissue homeostasis is maintained by a subtle balance between cell death on one side and cell proliferation on the other side, any changes in one of these parameters can form the basis for human diseases. The fact that under normal conditions apoptosis represents a safeguard mechanism to prevent tumorigenesis implies that evasion of apoptosis constitutes a characteristic feature of human cancers. Too little cell death contributes not only to cancer formation, but also to cancer progression and treatment resistance. A better understanding of the mechanisms that are involved in the regulation of apoptosis in human cancers over the last decades has led to the development of novel approaches for exploiting this cellular program for cancer therapy. Also, the elucidation of the molecular mechanisms that underlie the intrinsic apoptosis resistance of human cancers resulted in the identification of target structures that can be exploited for therapeutic purposes. For example, cell death is frequently impaired in cancers by aberrant expression of antiapoptotic proteins, for example "Inhibitor of Apoptosis" (IAP) proteins, which are expressed at high levels in many human cancers. Among the therapeutic approaches that have been developed to target IAP proteins, the most widely used strategy is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (Smac), which functions as an endogenous IAP antagonist. Current and future perspectives on targeting cell death pathways, for example by using Smac mimetics, for therapeutic intervention in human cancers will be discussed. Since antiapoptotic proteins of the BCL-2 family, including BCL-2, BCL-x_L and MCL-1, play a critical role in disabling the mitochondrial pathway of apoptosis, these antiapoptotic BCL-2 family proteins have gained a lot of attention for the development of mitochondria-targeted cancer therapeutics. To this end, structure-based, rational drug design has resulted in the development of small-molecule inhibitors of antiapoptotic proteins of the BCL-2 family. The concept to rationally target apoptosis signal transduction pathways has important implications for cancer therapy, since intact apoptosis programs are critical for the therapeutic efficacy of most anticancer therapies. Reactivation of apoptosis not only directly triggers cell death in cancer cells, but also lowers the threshold for apoptosis in response to other apoptotic stimuli, thus sensitizing tumor cells for apoptosis. In principle, the idea to target apoptosis pathways has been translated into first clinical applications. The challenge in future years will be to further exploit this concept for cancer therapy to the best possible extent.