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Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) (v.10, #10)
Editorial [Hot Topic : Targeting Focal Ahhesion Kinase in Cancer-Part I (Guest Editor: Vita M. Golubovskaya)] by Vita Golubovskaya (pp. 713-713).
I would like to thank you all authors for their excellent contribution to the Focal Kinase Adhesion issue. I would like to thank the journal editorial staff for their professional help in preparation of the issue. Focal Adhesion Kinase (FAK) is a 125 kDa protein that is localized at the focal adhesions. It plays a significant role in motility, adhesion, survival, proliferation, metastasis, angiogenesis and lymphangiogenesis. FAK has three domains: N-terminal with y397 autophosphorylation site, Kinase domain with ATP binding site and Y576/Y577 tyrosines, critical for protein activation and kinase function and also C-terminal domain with Y925 tyrosine and others sites, including many focal adhesion protein binding sites, such as paxillin, Grb-2, talin. Focal Adhesion Kinase is overexpressed in many types of tumors and recently has been proposed to be a therapeutic target. The authors summarize most of the known, published inhibitors of FAK that have been used in different cancer types. This issue contains several reviews that are focused on the role of FAK in different types of cancers. The review of Dr. Vita Golubovskaya summarizes data on expression of FAK in different tumor types and highlights different inhibitors of FAK. It includes data on immunohistochemical staining of FAK in different types of tumors and correlation with the patient prognostic factors. The review of Dr. Deniz A. Ucar and Steven N. Hochwald describes FAK expression and its role in pancreatic cancer. The authors describe association of FAK and IGFR-1 and extracellular matrix in pancreatic cancer. The authors show the data on the effect of FAK inhibitors on pancreatic cancer. The review of Dr. Gillory and Beierle is focused on the role of Focal Adhesion Kinase in neuroblastoma. It shows that inhibition of FAK can be a novel therapeutic approach in neuroblastoma. The authors demonstrate the effective inhibition of neuroblastoma cell growth with Y15 autophosphorylation inhibitor in contrast to the normal cells. The authors show the link of FAK and VEGFR signaling in neurobalstoma cells and demonstrate the anti-tumor effect of the inhibitor targeting FAK and VEGFR signaling. The review of Dr. Ko et al. and#x201C;Focal Adhesion Kinase as a therapeutic Target of bortezomiband#x201D; is focused on the novel effect of bortezomib on Focal Adhesion expression. The authors have excellent data on transcriptional repression of FAK by bortezomib through inhibiting NFkappaB binding to the FAK promoter. The authors suggest a potential targeting of FAK with bortezomib as a strategy to prevent tumor growth and metastasis. The review of Dr. Bullard Dunn et al. summarizes different therapeutic approaches in surgical oncology. The authors describe different cell cycle inhibitors, inducers of apoptosis, angiogenesis and FAK inhibitors and present mechanism and rational of using these inhibitors. The authors describe novel FAK inhibitors that are tested or presently evaluated in the ongoing clinical trials (http://www.clinicaltrials.gov/). In conclusion, these reviews summarize the importance of FAK in cancer cell survival and present evidence on the FAK as a therapeutic target. Future, clinical studies and clinical trials will present more data on FAK inhibitors as a first step for its clinical use. I would like to thank again all authors who contributed to this issue.
Targeting Focal Adhesion Kinase in Neuroblastoma by Lauren Gillory, Elizabeth A. Beierle (pp. 714-721).
Neuroblastoma is the most common extracranial solid tumor encountered in children, and continues to carry a dismal prognosis. Focal adhesion kinase (FAK) has been shown to be upregulated in a number of human tumors and is related to tumor virulence and patient prognosis. We have demonstrated FAK expression in human neuroblastoma cell lines and tumors, and have shown that FAK is important for neuroblastoma tumor cell viability. We have also demonstrated that FAK inhibition through a number of different methods results in decreased neuroblastoma survival both in vitro and in vivo. The current review addresses the merit of further exploring FAK inhibition as a novel treatment for neuroblastoma.
Evolving Therapies and FAK Inhibitors for the Treatment of Cancer by Kelli Bullard Dunn, Melissa Heffler, Vita M. Golubovskaya (pp. 722-734).
Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK).
Focal Adhesion Kinase as a Cancer Therapy Target by Vita M. Golubovskaya (pp. 735-741).
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that resides at the sites of at focal adhesions. The 125 kDa FAK protein is encoded by the FAK gene located on human chromosome 8q24. Structurally, FAK consists of an amino-terminal regulatory FERM domain, a central catalytic kinase domain, and a carboxy-terminal focal adhesion targeting domain. FAK has been shown to be an important mediator of cell adhesion, growth, proliferation, survival, angiogenesis and migration, all of which are often disrupted in cancer cells. Normal tissues have low expression of FAK, while primary and metastatic tumors significantly overexpress this protein. This review summarizes expression of FAK by immunohistochemical staining in different tumor types and presents several FAK inhibition therapy approaches.
FAK and Interacting Proteins as Therapeutic Targets in Pancreatic Cancer by Deniz A. Ucar, Steven N. Hochwald (pp. 742-746).
Pancreatic cancer is the fourth leading cause of cancer death in the United States. Chemotherapy and radiation therapy have had minimal ability to alter the natural course of the disease. Clearly, additional agents are needed to improve outcomes in this aggressive cancer. Pancreatic cancer has been found to have several genetic alterations including activation of K-ras and inactivation of p53, p16, and DPC4. Other alterations include upregulation of angiogenic factors and matrix metalloproteinases, dysregulation of growth factor receptors, and cytoplasmic kinases including focal adhesion kinase (FAK) and src. Clinicians must translate the available knowledge of the molecular basis of this disease into rationale and effective therapeutic strategies for treatment. The role of FAK in the pathogenesis of pancreatic cancer is discussed below and efforts aimed at the development of inhibitors of FAK for this disease are reviewed.
Focal Adhesion Kinase as a Therapeutic Target of Bortezomib by Bor-Sheng Ko, Tzu-Ching Chang, Jun-Yang Liou (pp. 747-752).
Bortezomib, a modified dipeptidyl boronic acid, is a selective potent proteasome inhibitor that has been approved for clinical treatment of multiple myeloma and mantel cell lymphoma. Results from a growing number of basic studies and clinical trials reveal that bortezomib could be used to treat diverse types of solid tumors alone or in combination with other chemotherapeutic drugs. It has been shown that bortezomib transcriptionally suppresses focal adhesion kinase (FAK) expression by interrupting the nuclear factor kappa B (NFand#954;B) pathway, which suggests that FAK could be a potential molecular target for bortezomib. Analysis of FAK promoter sequences revealed that FAK promoter harbors the NFand#954;B and p53 binding domains. Further studies of FAK promoter activity, real-time PCR, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay revealed that bortezomib inhibits NFand#954;B binding on the FAK promoter, thereby reducing FAK expression. Thus, bortezomib could inhibit cancer cell growth and migration or invasion by repressing FAK expression. Since activation and overexpression of FAK has been implicated in the progression and invasion of malignant tumors, it is likely that targeting FAK with bortezomib is a potential strategy for preventing cancer metastasis. This review focuses on the molecular regulation of FAK and the potential clinical application of bortezomib.
Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation by Carlos Mas-Moruno, Florian Rechenmacher, Horst Kessler (pp. 753-768).
Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors. This drug is the first anti-angiogenic small molecule targeting the integrins and#945;vand#946;3, and#945;vand#946;5 and and#945;5and#946;1. It was developed by us in the early 90s by a novel procedure, the spatial screening. This strategy resulted in c(RGDfV), the first superactive and#945;vand#946;3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor and#945;IIband#946;3. This cyclic peptide was later modified by N-methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf(NMe)V). This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany). This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials. The positive anti-angiogenic effects in cancer treatment can be further increased by combination with and#x201C;classicaland#x201D; anti-cancer therapies. Several clinical trials in this direction are under investigation.
Evaluation of Effect of Triterpenes and Limonoids on Cell Growth, Cell Cycle and Apoptosis in Human Tumor Cell Lines by Cristiane M. Cazal, Kantima Choosang, Vanessa Gisele P. Severino, Marcio S. Soares, Andre Lucio F. Sarria, Joao B. Fernandes, Maria Fatima G.F. Silva, Paulo Cezar Vieira, Pannee Pakkong, Gabriela M. Almeida, M. Helena Vasconcelos, Maria S.J. Nascimento, Madalena M.M. Pinto (pp. 769-776).
Six triterpenes and eight limonoids were evaluated for their capacity to inhibit the growth of three human tumour cell lines, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and melanoma (A375-C5). The mechanisms involved in the observed cell growth arrest of the four most potent compounds were carried out by studying their effect in cell cycle profile and programmed cell death. The results showed that one triterpene (odoratol) and two limonoids (gedunin and cedrelone) caused cell cycle arrest while only the limonoids gedunin and cedrelone were found to be very potent inducers of apoptosis.