Purpose: Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically controlled process. Lysinespecific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono-and dimethyl-lysine 4 of histone 3 (H3K4), key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the reexpression of aberrantly silenced genes. Experimental Design: Human colorectal cancer cells were treated with the oligoamines and changes in mono-and dimethyl-H3K4 and other chromatin marks were monitored. In addition, treated cells were evaluated for the reexpression of the aberrantly silenced secreted frizzled-related proteins (SFRP) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model. Results: Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, cotreatment with low doses of oligoamines and a DNA methyltransferase inhibitor highly induces the reexpression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo. Conclusions: The use of LSD1-inhibiting oligoamine analogues in combination with DNA methyltransferase inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer. (Clin Cancer Res 2009;15(23):7217-28) Epigenetics refers to heritable changes in gene expression patterns that are not regulated by changes in the primary DNA sequence. In cancer, epigenetic silencing of gene expression, including of tumor suppressor genes, is a common occurrence (1) that is associated with abnormal DNA methylation patterns and changes in covalent histone modifications (2). The amino-terminal tails of histones are subject to several posttranslational modifications, including acetylation, phosphorylation, and methylation, which are closely tied to transcriptional regulation, DNA replication, and DNA repair (2). As shown by the regulation of histone acetylation by histone acetyltransferases and histone deacetylases (HDAC), the addition and removal of these posttranslational modifications is a dynamic process. A similar dynamic regulation occurs for histone methylation with histone methyltransferases for the addition of methyl groups, and we recently discovered families of enzymes for specific histone demethylation. The first of these demethylating enzymes identified was the lysine-specific demethylase (LSD1/KDM1; ref.3), a flavin adenine dinucleotide (FAD)-dependent amine oxidase, which interacts directly with CoREST and HDAC1/2 pro...

Chemotherapy is currently one of the most effective ways to treat metastatic cancers. However, of the various mechanisms that are involved in conferring resistance, upregulation of drug efflux ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1) and ABCG2, has become a major obstacle to cancer chemotherapy and seriously affects the clinical outcome. To date, at least 15 ABC drug transporters have been identified and characterized to transport and confer resistance to practically the entire spectrum of cancer drugs, causing multidrug resistance (MDR) in cancers. Unfortunately, despite decades of research, there is still no real solution to MDR. This review highlights some of the major findings, the roles and problems associated with MDR-linked ABC drug transporters in metastatic cancers and solid tumors, and the current strategies to improve the clinical outcome in cancer chemotherapy.

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 over expression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguanides that are potent inhibitors of LSD1, and induce the reexpression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of isosteric ureas and thioureas that are also potent inhibitors of LSD1. These compounds induce increases in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related proteins (SFRP) 2 and 5, and transcription factor GATA4. These compounds represent an important new series of epigenetic modulators with the potential for use as antitumor agents.

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Lower heart rate variability (HRV) is associated with a higher risk of cardiovascular events and mortality, although the extent of the association is uncertain. We performed a meta-analysis of cohort studies to elucidate the association between HRV and the risk of all-cause death or cardiovascular events in patients with cardiovascular disease (CVD) during a follow-up of at least 1 year. We searched four databases (PubMed, MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) and extracted the adjusted hazard ratio (HR) from eligible studies. We included 28 cohort studies involving 3,094 participants in the meta-analysis. Results revealed that lower HRV was associated with a higher risk of all-cause death and cardiovascular events; the pooled HRs were 2.12 (95% confidence interval [CI] = [1.64, 2.75]) and 1.46 (95% CI [1.19, 1.77]), respectively. In subgroup analyses, the pooled HR of all-cause death was significant for patients with acute myocardial infarction (AMI) but not for those with heart failure. The pooled HR for cardiovascular events was significant for the subgroup of patients with AMI and acute coronary syndrome but not for those with coronary artery disease and heart failure. Additionally, both time and frequency domains of HRV were significantly associated with risk of all-cause death and cardiovascular events in patients with CVD.

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Ataxia is one of the most devastating symptoms of many neurodegenerative disorders. As of today, there is not any effective treatment to retard its progression. Mesenchymal stem cells (MSCs) have shown promise in treating neurodegenerative diseases. We hereby report the results of a phase I/IIa clinical study conducted in Taiwan to primarily evaluate the safety, tolerability, and, secondarily, the possible efficacy of intravenous administration of allogeneic adipose tissue-derived MSCs from healthy donors. Six patients with spinocerebellar ataxia type 3 and one with multiple system atrophy-cerebellar type were included in this open-label study with intravenous administration of 10 6 cells/kg body weight. The subjects were closely monitored for 1 year for safety (vital signs, complete blood counts, serum biochemical profiles, and urinalysis) and possible efficacy (scale for assessment and rating of ataxia and sensory organization testing scores, metabolite ratios on the brain magnetic resonance spectroscopy, and brain glucose metabolism of 18-fluorodeoxyglucose using positron emission tomography). No adverse events related to the injection of MSCs during the 1-year follow-up were observed. The intravenous administration of allogeneic MSCs seemed well tolerated. Upon study completion, all patients wished to continue treatment with the allogeneic MSCs. We conclude that allogeneic MSCs given by intravenous injection seems to be safe and tolerable in patients with spinocerebellar ataxia type 3, thus supporting advancement of the clinical development of allogeneic MSCs for the treatment of spinocerebellar ataxias (SCAs) in a randomized, double-blind, placebo-controlled phase II trials.

Cognitive impairment across different cognitive domains was found in individuals with fibromyalgia compared with healthy controls. Mood states (depression and anxiety) may explain the heterogeneity across studies.