Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types. The key signaling system that regulates proliferation and migration of endothelial cells are vascular endothelium growth factor (VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with higher affinity and greater kinase activity, is more important in the direct regulation of angiogenesis, mitogenic signaling, and permeability-enhancing effects. VEGFRs are expressed at high levels in many types of human solid tumors, including glioma, lung, breast, renal, ovarian and gastrointestinal tract carcinomas. Inhibition of VEGFR has emerged as a potential therapy method for cancers and it has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib. Consequently, a number of small molecules with VEGFR inhibitory properties have been developed. Many of these have been evaluated as potent inhibitors and some are currently in clinical-trials for various angiogenic related disorders including inflammatory diseases, retinopathies and age related macular degeneration. This review reports various VEGF/VEGFR pathway inhibitors such as small molecules and monoclonal antibodies, along with their reported activities.
Receptor Tyrosine Kinases class I (RTK class I, EGF receptor family) constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand. In contrast, activation of HER2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligand-independent manner. EGFR and HER2 have now been validated as a clinically relevant target, and several different types of agents inhibiting these receptors are currently in development. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors. Several of the other erbB inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. This review reports various inhibitors, natural, small molecules and monoclonal antibodies, along with their reported activities for various members of erbB family. It will highlight the potential for the development of novel anti-cancer molecules.
Findings of this study for the first time suggest that arsenic and estrogen exposures cause increased cell growth and survival potentially through epigenetic inactivation of MLH1 resulting in decreased MLH1-mediated apoptotic response, and consequently increased cellular transformation.
Chronic exposures to arsenic and estrogen are known risk factors for prostate cancer. Though the evidence suggests that exposure to arsenic or estrogens can disrupt normal DNA methylation patterns and histone modifications, the mechanisms by which these chemicals induce epigenetic changes are not fully understood. Moreover, the epigenetic effects of co-exposure to these two chemicals are not known. Therefore, the objective of this study was to evaluate the effects of chronic exposure to arsenic and estrogen, both alone and in combination, on the expression of epigenetic regulatory genes, their consequences on DNA methylation, and histone modifications. Human prostate epithelial cells, RWPE-1, chronically exposed to arsenic and estrogen alone and in combination were used for analysis of epigenetic regulatory genes expression, global DNA methylation changes, and histone modifications at protein level. The result of this study revealed that exposure to arsenic, estrogen, and their combination alters the expression of epigenetic regulatory genes and changes global DNA methylation and histone modification patterns in RWPE-1 cells. These changes were significantly greater in arsenic and estrogen combination treated group than individually treated group. The findings of this study will help explain the epigenetic mechanism of arsenic- and/or estrogen-induced prostate carcinogenesis.
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