The polyphenolic phytoalexin resveratrol (RSV) and its analogues have received tremendous attention over the past couple of decades because of a number of reports highlighting their benefits in vitro and in vivo in a variety of human disease models, including cardio- and neuroprotection, immune regulation, and cancer chemoprevention. These studies have underscored the high degree of diversity in terms of the signaling networks and cellular effector mechanisms that are affected by RSV. The activity of RSV has been linked to cell-surface receptors, membrane signaling pathways, intracellular signal-transduction machinery, nuclear receptors, gene transcription, and metabolic pathways. The promise shown by RSV has prompted heightened interest in studies aimed at translating these observations to clinical settings. In this review, we present a comprehensive account of the basic chemistry of RSV, its bioavailability, and its multiple intracellular target proteins and signaling pathways. Antioxid. Redox Signal. 11, 2851–2897.

Chemotherapy-induced reduction in tumor load is a function of apoptotic cell death, orchestrated by intracellular caspases. However, the effectiveness of these therapies is compromised by mutations affecting specific genes, controlling and/or regulating apoptotic signaling. Therefore, it is desirable to identify novel pathways of cell death, which could function in tandem with or in the absence of efficient apoptotic machinery. In this regard, recent evidence supports the existence of a novel cell death pathway termed autophagy, which is activated upon growth factor deprivation or exposure to genotoxic compounds. The functional relevance of this pathway in terms of its ability to serve as a stress response or a truly death effector mechanism is still in question; however, reports indicate that autophagy is a specialized form of cell death under certain conditions. We report here the simultaneous induction of non-canonical autophagy and apoptosis in human cancer cells upon exposure to a small molecule compound that triggers intracellular hydrogen peroxide (H₂O₂) production. Whereas, silencing of beclin1 neither inhibited the hallmarks of autophagy nor the induction of cell death, Atg 7 or Ulk1 knockdown significantly abrogated drug-induced H₂O₂-mediated autophagy. Furthermore, we provide evidence that activated extracellular regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) are upstream effectors controlling both autophagy and apoptosis in response to elevated intracellular H₂O₂. Interestingly, inhibition of JNK activity reversed the increase in Atg7 expression in this system, thus indicating that JNK may regulate autophagy by activating Atg7. Of note, the small molecule compound triggered autophagy and apoptosis in primary cells derived from patients with lymphoma, but not in non-transformed cells. Considering that loss of tumor suppressor beclin 1 is associated with neoplasia, the ability of this small molecule compound to engage both autophagic and apoptotic machineries via ROS production and subsequent activation of ERK and JNK could have potential translational implications.

Significance: Reactive oxygen species (ROS), generated by cells as side products of biological reactions, function as secondary messengers by impacting a host of cellular networks involved in maintaining normal homeostatic growth as well as pathological disease states. Redox-sensitive proteins, such as the tumor suppressor protein p53, are susceptible to ROS-dependent modifications, which could impact their activities and/or biological functions. Recent Advances: p53 is a transcription factor that controls a wide variety of target genes and regulates numerous cellular functions in response to stresses that lead to genomic instability. Thus, redox modifications of p53 could impact cell fate signaling and could have profound effects on pathways fundamental to maintaining cell and tissue integrity. Critical Issues: Recent studies present evidence that ROS function upstream of p53 in some model systems, while in others ROS production could be a downstream effect of p53 activation. Future Directions: In this review, we describe how ROS production regulates p53 activity and how p53 can, in turn, influence cellular ROS production. Antioxid. Redox Signal. 16, 1285–1294.