Editorial [ Apoptotic Pathways as Targets for Therapeutic Intervention Guest Editor: Domagoj Vucic ]

The evolutionarily conserved process of apoptosis plays an important role in removing cells during development and in maintaining tissue homeostasis. However, dysregulation of apoptosis, leading to too much or too little cell death, contributes to a number of diseases including cancer. Designing anti-cancer therapeutic solutions requires the understanding of the interplay between positive and negative regulators of the apoptotic program. Indeed, much has been learned about the molecular mechanisms of programmed cell death and the escape of tumor cells from apoptotic demise in recent years. These findings provide a foundation for novel drug design efforts that are poised to utilize newly acquired knowledge. Several of these strategies have already advanced to human clinical trials while many more are still tested in pre-clinical settings. Meulmeester and Jochemsen illustrate in great detail the role of p53 as a master regulator of apoptosis. Often called the guardian of the genome, the p53 tumor suppressor protein commands cell fate by controlling initiation of apoptosis, cell cycle arrest, senescence, and other seminal cellular processes. These authors examine complex mechanistic regulation of p53-induced apoptosis, and present evidence for both transcription independent and dependent pathways. Given the strong association of mutations in the p53 gene locus with occurrence of human tumors it is not surprising that p53 is one of the primary targets for anti-tumor therapeutic intervention. Increased understanding of its mechanistic and functional properties should enable development of p53-targeting anti-cancer agents. In their review Sarah MacKenzie and Clay Clarke dissect the role of caspases in apoptotic pathways. Caspases represent a convergent point of apoptotic pathways. As such, they are irreplaceable components of cell death machinery. The authors note that caspase activity is often diminished in tumor cells due to their decreased expression or inadequate activation. Thus, triggering the activation of caspases, especially effector caspases like caspase-3 that are the ultimate executors of cell death, might reduce tumor resistance to cytotoxic drug treatments. Dimerization of caspases is discussed as one of the targeting modalities since dimerization is essential for proper active site formation of all caspases. Hence, a small molecule that binds the dimer interface of procaspases and drives their activation could be useful in cancer treatment. In my review I discuss inhibitor of apoptosis (IAP) proteins and their role in cancer. IAP proteins are a family of anti-apoptotic regulators that block cell death in response to diverse stimuli. They are expressed in the majority of human malignancies at elevated levels and play an active role in promoting tumor maintenance through the inhibition of cellular death and participation in signaling pathways associated with malignancies. These features make them attractive targets for therapeutic intervention. Several IAP-targeting strategies are discussed, including small molecule IAP antagonists (SMAC mimetics), anti-sense RNAs, and immunotherapy. Maria Miasari, Hamsa Puthalakath and John Silke report on ubiquitylation and cancer development in their review. The Ubiquitin Proteasome System has garnered a lot of attention recently, and there is increased awareness of its importance in various cellular processes, including cell growth and death. The authors discuss the relevance of ubiquitylation and proteasomal degradation for tumor maintenance. Furthermore, they analyze in detail the proteasomal regulation of p53 and the Bcl-2 family of apoptotic regulators, as well as the proteasomal involvement in unfolded proteins-triggered ER stress in multiple myelomas. Tumor Necrosis Factor (TNF) and the TNF super-family as cancer therapeutics is the subject of the review by Dylan Daniel and Nick Wilson. Several ligands of the TNF super-family, including TNF-alpha, lymphotoxin, FAS ligand (FasL), and Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) have been tested in various stages of clinical research for their anti-tumor efficacy. Moreover, several antibodies to TNF receptor (TNFR) super-family members are now being explored as cancer therapeutics. The authors integrate the results of pre-clinical and clinical trials with a concise synopsis of the TNF signaling network, and attempt to reconcile our understanding of how the cell biology and tumor biology relate mechanistically. In her review, Simone Fulda focuses on the modulation of Apo2L/TRAIL-induced apoptosis by HDAC inhibitors. Apo2L/TRAIL, a member of the TNF super-family of death inducing ligands, is of special interest for cancer therapy as it predominantly kills cancer cells while sparing normal cells. Many cancers, however, fail to undergo apoptosis in response to Apo2L/TRAIL treatment. Thus, combination therapies are needed for cancer-specific sensitization towards Apo2L/TRAIL. In recent years, HDAC inhibitors (HDACI) that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells to Apo2L/TRAIL-induced apoptosis. Simone discusses recent advances in the understanding of the molecular events that underlie the synergistic interaction of HDACI and Apo2L/TRAIL as well as ways of translating this knowledge into the design of novel cancer-selective therapeutics. In conclusion, the review articles in this issue of Current Cancer Drug Targets are intended to provide instructive and thought-provoking analyses of apoptotic pathways, together with an in-depth examination of their usability as targets for therapeutic intervention in human malignancies.