oa Editorial [Hot Topic: Pharmaceutical Reactivation of p53 Pathways in Cancer (Executive Guest Editor: Asfar S. Azmi)]

P53 was discovered 30 years ago and research during the last three decades has produced over 55,000 publications leading to deeper understanding of this crucial protein [1]. Majority of cancers have dysfunctional p53, either through mutation of the p53 gene itself or alterations in factors that modulate p53's stability and activity. This has led to numerous strategies to combat cancer by re-activating p53 or related pathways in tumor cells [2]. Although much has been accomplished in understanding the regulation of its activity, there is still much to learn regarding the re-activation of p53 pathways. Gene therapy strategies such as the use of p53 adenovirus that selectively kill p53 deficient cells and pharmaceutical agents that induce conformational change in re-shaping the mutant p53 to enhance DNA binding are currently being pursued all around the globe [3]. However, in over half of cancers, wild type p53 is functional, but is tightly regulated by interacting with MDM2 (or the human homologue, HDM2) [4]. Genetic approaches to decrease the expression of MDM2 or development of synthetic peptides that target MDM2 are steadily developing [5]. From a pharmaceutical perspective, small molecular weight inhibitors have been demonstrated to disrupt the MDM2-p53 interaction without causing damage to the genome [6]. Such chemicals have been discovered by high-throughput screening methods and computational techniques based on crystal structure of MDM2-p53 interaction. A newer, more comprehensive approach is systems biology and network modeling which incorporates most of the published literature on the subject with results from cell-based assays to develop models which then can be verified and tested further in cell-based assays and in animals [7]. Pharmaceutical agents which promote wild type p53 re-activation are mainly small chemical molecules that inhibit the interaction between p53 and its regulator MDM2. These small molecules can potentially target p53 directly or target MDM2, either action resulting in the disruption of MDM2-p53 interaction and initiate the re-activation of p53 functional activity. More recently, interest has been generated in understanding the effect of these small molecules on other p53 family members, p63 and p73, which, in the absence of functional p53, may act through salvage pathways to effect a similar outcome; cell cycle arrest or cell death in tumor cells. Whether future pharmaceutical research will include the development of new agents to directly target p53-MDM2 interaction and agents that initiate the activation of pathways such as p73, independent of p53, will depend upon interaction of scientists with expert knowledge, sound data and future ideas expressed as a theme in this issue. This interaction is critical for the development of pharmaceutical agents to be successfully utilized as a single cure, in a preventative regimen or as adjuvants to reduce the necessary toxic chemotherapeutics presently used as anti-cancer agents. This theme issue is comprised of a collection of highly informative reviews from recognized experts in the area of p53 research. The list of thought provoking articles begins with a comprehensive update from Dr. Nouri Neamati's group on current status of small molecule inhibitors of HDM2 in their pre-clinical and clinical development. In the second article, Drs. Shen and Maki update the audience, through a very informative review on the current trends in p53 reactivating drugs, giving special emphasis to Nutlin-3. This is followed by an article from Dr. Zauli's group on therapeutic perspective on MDM2 inhibition by Nutlin-3 and their chemotherapy combination. In this article, readers can gain insight on the synergistic combinations of Nutlin-3 with novel drugs such as genotoxic platinum chemotherapeutics and TRAIL. In the next review, Drs. Bisso and Del Sal describe the significance of p73 as a critical therapeutic partner in the p53 pathway. Their article is an overview of the principal mechanism of p73 regulation, and describes several examples of pharmacological tools that can induce p73 accumulation and activate function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. The fifth review, contributed by Dr. Slade, comprehensively highlights that p53 family member p73 is equally important and its potential cannot be ignored while designing pharmaceutical dugs. This contribution discusses how understanding the role of p73 has affected drug discovery and outlines current aspects of anticancer therapy. Then, Drs. Changyou Zhan and Wuyuan Lu elaborate on the emerging concept of peptide based MDM2 and MDMX inhibition for the treatment of cancer. In review number seven of this theme issue, Dr Park and group, describe a novel p53 inactivation mechanism by oncogenic K-Ras-Snail axis and a smart strategy to overcome this suppressive mechanism by chemical inhibition of snail-p53 interaction. Following this, Dr. Boyd and his team highlight the differential sensitivity of different tumors to p53 targeted regimens in review eight. Their article provides a clinical perspective and gives prominence to the understanding that not all tumors respond equally to p53 re-activating drugs. Dr. Athar, in his review, describes the potential of re-activating mut-p53 by natural agents, small molecule inhibitors and other strategies for cancer therapy. And finally, this special issue is concluded by an article from my group that describes the utility of systems biology and molecular network modeling in understanding the complex p53-HDM2 network. Our article builds a strong case for use of integrated technology in the design of optimal combination therapies involving HDM2 inhibitors and platinum based genotoxic agents. It is my opinion that this comprehensive collection of reviews from experts in the field encompassing wide ranging topics on pharmaceutical re-activation of p53 and related pathways is timely and will be definitely enhance the knowledge of the researchers actively engaged in the field. Therefore, I sincerely wish the audience enjoyable reading. ACKNOWLEDGEMENTS First and foremost, I would like to thank the Editor-in-Chief Dr. William A. Banks for giving me opportunity to organize this special theme issue. I would like to thank all of the contributing authors for their outstanding articles. I also would like to especially acknowledge all of the anonymous reviewers who kindly reviewed the articles. Dr. Irfana Muqbil's assistance in arranging peer review and proof reading the manuscripts is deeply acknowledged. I am indebted to the Editorial Director Mr. Mirza Kazim Ali Baig and the staff members of Bentham Science Publishers for their assistance in coordinating the publication of this special issue on Pharmaceutical Reactivation of p53 Pathways in Cancer in the journal Current Pharmaceutical Design.