Editorial [Hot Topic: Cancer Cell Redox Status: Novel Target for Designing Strategies to Overcome Apoptosis Resistance (Executive Editor: S. Pervaiz)]

Apoptosis is a highly conserved form of cell death, orchestrated by an intricate cross talk between intracellular cysteine proteases (caspases) and amplification factors released from the inter-membranous space of the mitochondria, such as cytochrome C, apoptosis inducing factor, Smac/DIABLO, HtrA2/Omi, and others. Efficient execution of the apoptotic signal is controlled by diverse intracellular mechanisms, ranging from transcriptional activation of genes involved in death signaling or the reciprocal repression of the death inhibitory genes (e.g. p53-induced transcription), to posttranslational modification of proteins and their intracellular trafficking (e.g. the Bcl-2 family). These pro-death forces are counteracted by parallel mechanisms to keep death in check, such as the anti-apoptotic members of the Bcl-2 family, transcription factors such as NF- κB, and activation of cell survival pathways such as the PI3K/Akt network. By dint of the critical role that apoptosis plays in tissue homeostasis and regulation of normal cell growth and proliferation, excessive or deficient apoptosis is an invariable finding in pathological disease states. This is particularly true during the process of cellular transformation and abnormal growth associated with the neoplastic phenotype. As a matter of fact, defect or deficiency somewhere in the apoptotic signal transduction machinery is an acquired hallmark of cancer cells. In the first article, S. Rodriguez-Nieto and B. Zhivotovsky [1] present a snapshot of the various alterations or aberrations in the apoptotic signaling circuitry, particularly in the context of carcinogenesis, and provide a logical basis for novel target-selective drug design to combat the problem of drug resistance in cancer cells. The link between genomic instability upon inactivation of essential gatekeeper genes of the p53 family or the inability to activate damage sensing systems and cancer is discussed. A synopsis of the data pertaining to the defects in receptor-mediated as well as mitochondria-dependent apoptotic signaling in cancer cells is presented as probable druggable targets for enhancing the efficacy of chemotherapy. G. Giles [2] provides an excellent commentary on the role of intracellular redox status in tailoring a milieu conducive for growth and proliferation. The author discusses the basis for the altered redox status of cancer cells and the involvement of reactive oxygen and reactive nitrogen species (ROS and RNS) in modulating the signal transduction pathways and transcription factors commonly associated with the malignant phenotype, particularly in relation to cell proliferation and apoptosis. In addition, differences in mitochondrial morphology, ROS generation, and bioenergetics, between normal and cancer cells are presented. The author proposes tumor redox status as a potential target for novel drug design. J. M. Tarr, P. Eggleton, and P.G. Winyard [3] present a comprehensive account of the role of nitric oxide (NO) in the regulation of apoptotic signaling in tumor cells. Depending upon the milieu, transduction pathways of NO may induce cytotoxicity but may also confer cell protection. The latter could be mediated via activation of signal transduction pathways involved in cell survival/proliferation and angiogenesis, or by blocking cell death signaling by inhibiting caspase activation, both of which could potentially favor the process of carcinogenesis. Alternatively, the death promoting activity of NO could be mediated via cross talk with p53 or through down-regulation of death inhibitory proteins belonging to the IAP family. Along similar lines, S. Pervaiz [4] dwells on the relationship between a prooxidant intracellular milieu and carcinogenesis. The author discusses the differential effects of intracellular superoxide and hydrogen peroxide on apoptotic signaling pathways, whereby a slight increase in intracellular superoxide favors cell survival by inhibiting apoptosis, whereas a significant increase in hydrogen peroxide creates a milieu permissive for death execution. This hypothesis is discussed in the light of recent data demonstrating the intermediary role of a pro-oxidant environment in oncogene-induced cell survival, using Bcl-2 and Rac1 as examples. In addition, the differential effect of superoxide and hydrogen peroxide is presented as a function of intracellular pH via targeting the Na+/H+ exchanger, thereby linking cytosolic acidification to an increase in sensitivity to apoptosis. The author proposes tumor intracellular redox status and pH as excellent novel targets for effective anti-cancer drug design.........