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View the Table of Contents for the September 1 issue of Cancer Research.
Lopez-Serra et al. Page 8342
Hypermethylation of promoter CpG islands is a widely accepted mechanism of inactivation of tumor-suppressor genes in cancer that actively contributes to tumorigenesis. However, little is known about the nuclear factors involved in translating the information encoded by DNA methylation to transcriptional silencing. Methyl-CpG binding domain (MBD) proteins constitute a key element in this scenario. Lopez-Serra et al. used a combination of chromatin immunoprecipitation, expression, and DNA methylation assays to define the profile of MBD occupancy in human cancer cells. This study indicates that MBDs have a great affinity in vivo for binding hypermethylated promoter CpG islands of tumor suppressor genes, with a specific profile of MBD occupancy that it is gene- and tumor-type specific.
Campbell et al. Page 8707
Statins are cholesterol-lowering drugs with pleiotropic activities, including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. Campbell et al. evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. They also examined the in vivo impact of statin administration in a mouse ErbB2+ breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also appears associated with reduced tumor cell proliferation and survival.
Page 8715
The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. Small molecule inhibitors of VEGF receptors have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. Polverino et al. show that oral administration of a novel nicotinamide, AMG 706, potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. Histological analysis revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.
Page 8903
Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA)-pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. Cimino et al. assessed the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. VPA-ATRA treatment was well tolerated and induced phenotypic changes of AML blasts through chromatin remodeling. This study provides the first in vivo evidence for a biological effect of VPA-ATRA treatment in reprogramming the leukemic clone through chromatin remodelling and highlights the potential use of epigenetic approaches for the treatment of AML.