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Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) (v.11, #7)
Editorial [Hot topic: Focal Adhesion Kinase Signaling in Cancer- Part II (Guest Editor: Vita M. Golubovskaya)] by Vita M. Golubovskaya (pp. 591-592).
I would like to thank all the authors for their excellent contributions to the Focal Adhesion Kinase Signaling issue. I would also like tothank the journal for the invitation and the editorial staff for their expert help in the preparation of the second part of this issue.Focal Adhesion Kinase (FAK) is a 125 kDa protein that is localized at the focal adhesions. It plays a significant role in adhesion, motility,invasion, survival, proliferation, metastasis, angiogenesis and lymphangiogenesis. Focal Adhesion Kinase is a cytoplasmic protein, butrecently has been found to have novel functions in the nucleus. The authors of this issue summarize the novel functions and interactions andcross-talk of Focal Adhesion Kinase with other signaling pathways in cancer cells. This issue is interesting and important for the developmentof new therapies, as it summarizes data and literature in different model organisms, such as Xenopus laevis, Drosophila melanogaster, Homosapiens and describes FAK signaling in different types of cancer: colon, esophageal, prostate, breast, pancreatic and lung cancers. This issuealso discusses the interaction of FAK with important signaling pathways such as p53, IGF-1R, AKT, ERK1/2, HA/HAS3, WNT3, Pax-5 andLgl/Hugl pathways in different cancer cells.The review of Vita M. Golubovskaya and William G. Cance summarizes the data on the nuclear function of FAK and the novelinteraction of FAK with p53 that the authors first discovered in 2005 (Golubovskaya et al., JBC, 2005). The authors discuss the fact that FAKcan inhibit the transcriptional activity of p53 through direct interaction with p53 protein, and that p53 can block the transcription of FAKthrough binding to the FAK promoter. There is feed forward loop regulation between FAK and p53 pathways and balance to regulate survivalof cancer cells. The authors discuss the fact that targeting this interaction can be very important for cancer therapy.The paper of Teng et al. demonstrates data that inhibition of the HAS3 pathway in colon cancer decreased colon cancer growth byincreasing apoptosis. It is known that hyaluronan (high molecular cell surface glycisaminoglycan) and hyaluronan syntases have beenimplicated in cancer growth. It is also known that FAK and HA signaling inter crossed and HA can stimulate FAK signaling. The authorsrecently found that FAK and HA pathways interact in colon cancer. Also, Focal Adhesion Kinase is known to be overexpressed in coloncancer. The authors show that inhibition of HAS signaling increased apoptosis and blocked HCT116 colon cancer tumor growth. The authorsdiscuss the intersection of HA-CD44 and FAK pathways in colon cancer and inhibitors of the HA pathway for colorectal therapy in clinicaltrials. The combination of FAK and HAS inhibitors would be interesting to test in future studies.The review of Figel and Gelman is focused on the role of Focal Adhesion Kinase in prostate cancer. The authors discuss thekinase-dependent function of FAK in prostate cancer, summarize data on its expression in vitro and in vivo models and discuss inhibitors ofFAK.The paper of Ucar et al. demonstrates data on novel inhibitor of FAK and IGF-1R interaction in esophageal cancer. The authors used acomputer modeling approach to target FAK and IGF-1R interaction and found one small molecule that dose-dependently disrupted thisinteraction, decreased down-stream AKT and ERK1/2 pathways and blocked esophageal tumor growth in vivo. The authors discuss the factthat targeting FAK and IGF-1R canThe review of Fonar and Frank summarizes the data on a novel pathway and crossing of FAK and WNT pathways in the developmentcancer. The authors discuss their novel data on Xenopus laevis, where depletion of FAK protein eliminated WNT3a expression in the neuralplate. The authors discuss the fact that in the mouse intestine FAK activity was induced down-stream of WNT, which was critical for tumorgenesis. The authors discuss FAK and WNT interactions in lung, breast, pancreatic, and other cancer types.The review of Weisman and Golubovsky summarizes data on cross-linking pathways of Drosophila protein DFak56 (ortholog ofhuman FAK) and Lgl pathways. The authors compare the functions of two cancer-related proteins that are both involved in the formation ofmacromolecular complexes mediated by phosphorylation. Both of the proteins play an important role in cell adhesion, cell motility andproliferation. The authors show that under stress conditions (permanent thermal stress) the viability and life span of lgl*/lgl+ heterozygotesincreased compared to control groups and that this effect was maternally mediated and males were more sensitive to stress. This analysis isunique and shows that the Drosophila model and ontology comparison approach can be important for anti-cancer therapy and development ofanti-cancer drugs.The review of Crapoulet et al., discusses the role of Paired box protein PAX-5 and FAK in metastasis. The PAX5 gene is a member of thePAX family transcription. The Pax-5 gene encodes a B-cell lineage specific activator (BSAP) protein that is involved in B lymphocytedifferentiation and embryogenesis. The authors discuss direct and indirect regulation of FAK by Pax-5. The direct regulation can occurthrough direct binding of PAX-5 to the FAK promoter where Pax-5 represses FAK expression. The indirect regulation of FAK can occurthrough Src and calpain signaling that are effected by Pax-5. The authors discuss the role of PAX-5 and FAK in mesenchymal to epithelialtransition (MET) process, where PAX-5 inhibits FAK allowing cancer cells to mediate this transition and facilitate metastasis.The review of Schultze and Fiedler summarizes data on FAK inhibitors and development of anticancer drugs. The authors review severalinhibitors that are in clinical trials and discuss the data of Phase I trials. In addition, the authors show data on the important role of FAK inangiogenesis.The review of Ma is focused on data of different small molecule inhibitors that are developed for targeting FAK. The author summarizesdata on a novel class of FAK inhibitors not targeting ATP-binding site: allosteric FAK inhibitors: Y15 and C4. The first inhibitor targets theY397 autophosphorylation site of FAK and the second inhibitor targets FAK and VEGFR-3 interaction. The author suggests that FAK inhibitors may be best used in combination therapy and concludes that clinical development of FAK inhibitors has the potential for cancerpatient treatment programs.In conclusion, these papers and reviews demonstrate the importance of FAK and other signaling pathways in cancer cell survival andpresent data on the FAK as a therapeutic target.
Clinical Importance and Potential Use of Small Molecule Inhibitors of Focal Adhesion Kinase by Alexander Schultze, Walter Fiedler (pp. 593-599).
Since its first description Focal Adhesion Kinase (FAK), a cytoplasmatic tyrosine kinase, has been implicated in the formationand progression of solid and liquid malignant tumors. Therefore orally available selective small molecule inhibitors of FAK have beendeveloped, three of them (PF-562-271, PF-04554878 and GSK2256098) are already in clinical testing. This review discusses the recentdata obtained from these Phase 1 trials. We also discuss available data on the mechanisms of action of these inhibitors in carcinogenesisand demonstrate that FAK plays an important role in neoangiogenesis which is a crucial step in cancer growth.
FAK and WNT Signaling: The Meeting of Two Pathways in Cancer and Development by Yuri Fonar, Dale Frank (pp. 600-606).
Recent studies connect the FAK and Wnt/β-catenin signaling pathways, both which promote cancer when aberrantly activatedin mammalian cells. Over-stimulation of either Wnt/β-catenin or FAK activities was independently shown to promote numerous types ofhuman cancers, including colon, breast, prostate and ovary. Observations in different model systems suggest a complex and dynamiccross-talk between these two pathways. During early vertebrate development, FAK protein is required for the proper regulation of Wnt/β-catenin signaling that controls pattern formation in the developing nervous system. In Xenopus laevis embryos, FAK protein depletioneliminated Wnt3a gene expression in the neural plate. In mouse osteoclast cells, mechanical stimulation through FAK activation stabilizedβ-catenin protein to promote its nuclear translocation. In contrast, in the mouse intestine, FAK activity was induced downstream ofWnt to promote intestinal regeneration and was also essential for tumorigenesis in an APC deletion model of colorectal cancer. Adding tothis complexity, in human cell lines, FAK induced a context-dependent modulation of Wnt signaling to activate target-gene expression.Other diseases are also associated with FAK and Wnt pathway over-activation. Increased FAK and Wnt pathway activities were independentlyimplicated in idiopathic pulmonary fibrosis (IPF), a lung disease of unknown etiology. Revealing the FAK-Wnt connection inIPF could provide a better understanding of disease pathology. There appear to be multiple interactions between the Wnt/β-catenin andFAK signaling pathways in different cell types and organisms. Mutual FAK-Wnt pathway regulation could be a general phenomenon,having many still undetermined roles in either normal physiological or disease processes.
Focal Adhesion Kinase Controls Prostate Cancer Progression Via Intrinsic Kinase and Scaffolding Functions by Sheila Figel, Irwin H. Gelman (pp. 607-616).
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which mediates integrin signaling from the sites of connectionto the extracellular membrane known as focal adhesions. FAK mediates essential cellular processes including growth, proliferation, adhesion,migration, and survival through its functions as a molecular scaffold and as a kinase. FAK is frequently overexpressed and overactivein prostate cancer, which represents the second leading cause of cancer deaths in American men. Through the activation of majoroncogenic pathways, FAK promotes the growth, survival, migration, metastasis, and androgen-independence of prostate tumors in vitroand in vivo. A full examination of FAK kinase function has never been completed despite many studies suggesting its importance and thedevelopment of kinase-specific therapeutic inhibitors. An expanded understanding of FAK kinase function is required to understand therole of FAK in prostate cancer progression, thereby aiding future development of novel inhibitory drugs and screening procedures.
FAK and p53 Protein Interactions by Vita M. Golubovskaya, William G. Cance (pp. 617-619).
Focal Adhesion Kinase plays a major role in cell adhesion, motility, survival, proliferation, metastasis, angiogenesis andlymphangiogenesis. In 2004, we have cloned the promoter sequence of FAK and found that p53 inhibits its activity (BBA, v. 1678, 2004).In 2005, we were the first group to show that FAK and p53 proteins directly interact in the cells (JBC, v. 280, 2005). We have shownthat FAK and p53 proteins interact in the cytoplasm and in the nucleus by immunoprecipitation, pull-down and confocal microscopyassays. We have shown that FAK inhibited activity of p53 with the transcriptional targets: p21, Bax and Mdm-2 through protein-proteininteractions. We identified the 7 amino-acid site in p53 that is involved in interaction with FAK protein. The present review will discussthe interaction of FAK and p53 proteins and discuss the mechanism of FAK-p53 loop regulation: inhibition of FAK promoter activity byp53 protein and also inhibition of p53 transcriptional activity by FAK protein.
Inhibition of Hyaluronan Synthase-3 Decreases Subcutaneous Colon Cancer Growth by Increasing Apoptosis by Brian P. Teng, Melissa D. Heffler, Eric C. Lai, Ya-Li Zhao, Charles M. LeVea, Vita M. Golubovskaya, Kelli M. BullardDunn (pp. 620-628).
Hyaluronan (HA) and hyaluronan synthases (HAS) have been implicated in cancer growth and progression. We previouslyhave shown that HAS3 and HA mediate tumor growth in SW620 colon cancer cells, but the mechanism remains poorly understood. Inaddition, the effect of HAS3 inhibition on tumor growth with other cells lines has not been explored. We therefore hypothesized that inhibitionof HAS3 in highly tumorigenic HCT116 colon cancer cells would decrease tumor growth and that the underlying mechanismwould involve altering proliferation and/or apoptosis. HAS3 expression was inhibited by transfection with siRNA; a scrambled sequenceserved as a control. Stable transfectants were injected into the flanks of nude mice and tumor growth followed for 30 days. Proliferationand apoptosis were then assessed in the harvested tumors. Results were compared using the Students’ t-test and ANOVA where appropriate.siRNA transfection decreased HAS3 expression, protein production, and pericellular HA retention, and decreased in vivo tumorgrowth. Proliferation was unaffected in the HCT116 tumors, but increased slightly in the SW620 tumors. In contrast, HAS3 inhibitionsignificantly increased apoptosis in all tumors. HAS3 inhibition decreases subcutaneous tumor growth by colon cancer cells and significantlyincreases apoptosis with less effect on proliferation. These data show that HAS3 and HA mediate colon cancer growth by inhibitingapoptosis.
A Novel Small Molecule Inhibitor of FAK and IGF-1R Protein Interactions Decreases Growth of Human Esophageal Carcinoma by Deniz A. Ucar, Audrey Cox, Di-Hua He, David A. Ostrov, Elena Kurenova, Steven N. Hochwald (pp. 629-637).
Introduction: Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two importanttyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novelsmall molecule compound that disrupts FAK and IGF-1R protein-protein interactions (PPIs) would decrease the growth of human esophagealcancer.Methods: The compound INT2-31 (NSC344553) was identified from a virtual high throughput screen to bind to FAK and disrupt PPIs.The in vitro effects of this compound, +/- 5-FU chemotherapy, on cell signaling, viability and apoptosis in human esophageal cancer cells(KYSE 70, 140) and a direct esophageal cancer xenograft was evaluated.Results: INT2-31 caused a disruption of PPIs between FAK and IGF-1R starting at a concentration of 1iM. It also caused a dose dependentinhibition of cell viability and induction of apoptosis at low micromolar doses. These effects were associated with decreased AKTand ERK1/ERK2 phosphorylation. INT2-31 treatment, when administered via IP injection, at 50mg/kg, resulted in an in vivo decrease intumor growth in a direct xenograft. Furthermore, treatment with 5-FU chemotherapy combined with INT2-31 resulted in a synergistic increasein apoptosis and decrease in tumor growth compared to 5-FU or INT2-31 alone.Conclusions: A novel compound that disrupts the PPIs of FAK and IGF-1R results in decreased tumor proliferation and increased apoptosis.These effects appear to be mediated through downregulation of p-AKT and p-ERK. This compound deserves further study as anovel treatment strategy in patients with esophageal cancer.
Development of Focal Adhesion Kinase Inhibitors in Cancer Therapy by Wen Wee Ma (pp. 638-642).
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase implicated in cancer progression, and plays a vital role inintegrating environmental signals from growth factors, extracellular matrix and mechanical forces. As a scaffolding protein, FAKinteracts and regulates the activity of many signaling kinases including Src, VEGFR-3, p53, PI3k and IGF-1R. In turn, FAK activity ismodulated by a complex network of regulators that presents a number of therapeutic approaches to targeting FAK in cancer therapy. TheATP competitive inhibitors binds directly to FAK kinase domain to abrogate multiple downstream signaling pathways, and this class ofagents lead the way in FAK inhibitor clinical development. CFAK-C4 and Y15 represents a novel class of non-ATP dependant, allostericinhibitors that interrupt protein-protein interactions to achieve anti-cancer effects. The optimal approach to targeting FAK for cancertherapy is currently under investigation. Preliminary efficacy signals from early-phase trials suggest that FAK inhibitors may be bestused in combination therapy. In addition to determining dosing schedules that is tolerable by patients, future clinical studies shouldinclude mechanistic-based pharmacodynamic studies to determine the biological active dose and explore potential predictive markers. Insummary, a rich pipeline of FAK-targeting agents is entering clinical development and has the potential of improving the lives of cancerpatients.
Coordinated Expression of Pax-5 and FAK1 in Metastasis by Nicolas Crapoulet, Pierre O’Brien, Rodney J. Ouellette, Gilles A. Robichaud (pp. 643-649).
The Pax-5 gene encodes a B-cell-specific activator protein (BSAP) that plays a key role in B lymphocyte differentiation andembryogenesis. The deregulation of this transcription factor is also linked to B cell malignancies and recently to other cancers. More specifically,the downstream effects of Pax-5 promote cell-cell interactions and mediate the activation of adhesion genes which result in anepithelial phenotypic behavior of human carcinoma cells. To gain a better understanding of Pax-5-mediated gene regulation, we studiedavailable gene expression data in depth and identified several Pax-5 downstream targets. Among these, we found that Pax-5 activityis consistently inversely correlated with the expression of Focal Adhesion Kinase 1 (FAK1). FAK1 is known to enhance migrationof cancer cells and promote metastatic dissemination to distant sites. Further analysis looking at genome wide profiling of Pax-5 DNAbindingpoints to both direct and indirect regulation of FAK1 expression by Pax-5 and its downstream targets. These findings suggest akey role for Pax-5 in phenotypic transitioning during metastasis through the regulation of FAK1 activity.
Cell Contact/Adhesion Proteins Lgl and DFak56: Tumorigenic and Whole-Organism Vital Effects Studied in Drosophila by Nataly Ya. Weisman, Michael D. Golubovsky (pp. 650-657).
Drosophila modeling can be effectively used for comprehensive and refined analysis of tumorigenesis, including the discoveryof therapeutic anti-cancer drugs and their testing [1]. The Drosophila lgl gene was the first animal tumor suppressor found and the firsttumor-associated gene encoding cytoplasmic protein. We compared the gene ontology of two cancer-associated cytoplasmic proteins,Lgl and DFak56 (ortholog of human focal adhesion kinase, FAK). On the molecular level, both Lgl and FAK are involved in proteinbinding and the formation of macromolecular complexes mediated by phosphorylation in specific sites. On the cellular level, Lgl andFAK participate in cytoskeletal structure/dynamics, cell/ESM and cell to cell adhesion, and cell/tissue polarity. The biological processesof both genes comprise protein transport, cell signaling, cell motility and proliferation. Surprisingly, we found that diverse lgl*- nullvariants are widespread in lgl*-/lgl+ haplozygotic state in distant populations. To address this paradox, we found that under permanentthermal stress the developmental viability and the life span of lgl*-/lgl+ heterozygotes increased compared to the control flies. Thestress-protective haplo-adaptive effect was maternally mediated and sex-specific, as males are more sensitive. The exposure ofvirgin haplozygotic females with one functional lgl allele to pulse thermal stress at successive stages of oogenesis showed that thegerm line - early oocyte stage appeared most sensitive. Pulse heating of this stage in the parental females with one lgl dose resulted ina transgenerational haplo-adaptive effect on the viability and life span of the next generation animals. These data are important for acomprehensive knowledge of cancer-associated gene effects and evaluation of the aftermath of cancer therapy.
Recent Developments in the Mechanism of Anticancer Agents Based on Electron Transfer, Reactive Oxygen Species and Oxidative Stress by Peter Kovacic, Ratnasamy Somanathan (pp. 658-668).
Extensive evidence supports involvement of electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS)in the mechanism of many anticancer drugs. The common ET functionalities, usually present in the drug metabolites, are quinones (orprecursors), metal complexes (or complexors), hydroxylamine and nitroso from ArNO2 or ArNH2, and conjugated imines (or iminiumspecies). The ET agents function catalytically in redox cycling with formation of ROS from oxygen. Electrochemical data add support tothe mechanistic viewpoint. The generated metabolites generally possess reduction potentials amenable to ET in vivo, thus giving rise toROS. The resulting OS is a participant in destruction of the cancer cell. The action has been termed phagomimetic based on similarity tophagocytosis. It is important to recognize that drug action is often multipronged. The various modes of action are summarized.
Nanoparticles in Oncology: The New Theragnostic Molecules by Alessandro Allegra, Giuseppa Penna, Andrea Alonci, Vincenzo Rizzo, Sabina Russo, Caterina Musolino (pp. 669-686).
Cancer nanotherapeutics have shown promise in resolving some of the limitations of conventional drug delivery systems suchas nonspecific biodistribution and targeting, lack of water solubility, low therapeutic indices, and poor oral bioavailability. Moreover,cancer nanotechnology has the potential of improving current approaches to cancer detection, diagnosis, and imaging. Recently,nanotechnology and molecular imaging have been combined to generate nanoparticles that simultaneously facilitate cancer therapyand diagnosis, the so called theragnostic nanoparticles. The aim of our review is to highlight recent developments within the context ofthe current knowledge of nanotechnology, to recall the experimental steps that have brought to the clinical development and applicationof nanoparticles, and explain the biological rationale for their use with oncologic patients. In particular, we summarize recent findingswith respect to possible new applications for therapy and diagnosis, and their specific properties. Moreover, we report the more recentprospects in gene therapy, the possibility of using new drug delivery methods, the action of nanoparticles on the immune system andapoptosis, and the concrete possibility of detecting and characterizing circulating tumor cells or of developing new technologies in drugdiscovery.
Nitroimidazoles as Anti-Tumor Agents by Kai Liu, Hai-Liang Zhu (pp. 687-691).
At present cancer treatment is still a confusing problem. Great progress has been made in anti-tumor agents since a series ofsmall molecules are approved by FDA as anti-tumor drugs. Nitroimidazoles is a kind of radiosensitizer with multiple bioactivities used incancer treatment since 1950s. In this review, we focus on the development of nitroimidazoles as radiosensitizer, bio-reductive prodrugand other types of anti-tumor agents for cancer therapy, and the mechanism of acting as anti-tumor agents. Finally, we also discuss theprospect and developmental trend of nitroimidazoles as anti-tumor agents.