Showing papers by "Che-Hong Chen published in 2017"

ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective

Abstract: The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking. The global cancer deaths attributed to alcohol-consumption rose from 243,000 in 1990 to 337,400 in 2010. In 2010, cancer deaths due to alcohol consumption accounted for 4.2% of all cancer deaths. Strong epidemiological evidence has established the causal role of alcohol in the development of various cancers, including esophageal cancer, head and neck cancer, liver cancer, breast cancer, and colorectal cancer. The evidence for the association between alcohol and other cancers is inconclusive. Because of the high prevalence of ALDH2*2 allele among East Asian populations, East Asians may be more susceptible to the carcinogenic effect of alcohol, with most evidence coming from studies of esophageal cancer and head and neck cancer, while data for other cancers are more limited. The high prevalence of ALDH2*2 allele in East Asian populations may have important public health implications and may be utilized to reduce the occurrence of alcohol-related cancers among East Asians, including: 1) Identification of individuals at high risk of developing alcohol-related cancers by screening for ALDH2 polymorphism; 2) Incorporation of ALDH2 polymorphism screening into behavioral intervention program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals. Future studies should evaluate whether these strategies are effective for preventing the occurrence of alcohol-related cancers.

Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor

Abstract: // Jeewon Kim 1 , June Ho Shin 1, 2 , Che-Hong Chen 3 , Leslie Cruz 3 , Lovisa Farnebo 2, 4 , Jieying Yang 1 , Paula Borges 2 , Gugene Kang 5 , Daria Mochly-Rosen 3 and John B. Sunwoo 1, 2 1 Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, 94305, USA 2 Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University, Stanford, CA, 94305, USA 3 Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA, 94305, USA 4 Division of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, SE-58185, Linkoping, Sweden 5 Department of Developmental Biology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA Correspondence to: John B. Sunwoo, email: sunwoo@stanford.edu Keywords: aldehyde dehydrogenase, chemoresistance, head and neck squamous cell carcinoma, small molecule inhibitors Received: September 28, 2015 Accepted: March 30, 2017 Published: April 10, 2017 ABSTRACT Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease.

Aldehyde dehydrogenase 2*2 knock-in mice show increased reactive oxygen species production in response to cisplatin treatment

Abstract: The aldehyde dehydrogenase (ALDH) enzyme family metabolizes and detoxifies both exogenous and endogenous aldehydes Since chemotherapeutic agents, such as cisplatin, generate cytotoxic aldehydes and oxidative stress, and chemoresistant cancer cells express high levels of ALDH enzymes, we hypothesized that different ALDH expression within cells may show different chemosensitivity ALDH2 has the lowest Km for acetaldehyde among ALDH isozymes and detoxifies acetaldehydes in addition to other reactive aldehydes, such as 4-hydroxy-nonenal, malondialdehyde and acrolein produced from lipid peroxidation by reactive oxygen species (ROS) Thus, cells with an ALDH2 variant may sensitize them to these ROS-inducing chemotherapy drugs Here, we used wild type C57BL/6 mice and ALDH2*2 knock-in mutant mice and compared the basal level of ROS in different tissues Then, we treated the mice with cisplatin, isolated cells from organs and fractionated them into lysates containing mitochondrial and cytosolic fractions, treated with cisplatin again in vitro, and compared the level of ROS generated We show that overall ROS production increases with cisplatin treatment in cells with ALDH2 mutation The treatment of cisplatin in the wild type mice did not change the level of ROS compared to PBS treated controls In contrast, ALDH2*2 knock-in mutant mice showed a significantly increased level of ROS compared to wild type mice in tongue, lung, kidney and brain tissues without any treatment ALDH2*2 mutant mice showed 20% of the ALDH2 activity in the kidney compared to wild type mice Treatment of ALDH2*2 mutant mice with cisplatin showed increased ROS levels in the mitochondrial fraction of kidney In the cytosolic fraction, treatment of mutant mice with cisplatin increased ROS levels in lung and brain compared to PBS treated controls Furthermore, ALDH2*2 mutant mice treated with cisplatin showed increased cytotoxicity in the kidney cells compared to PBS treated mutant controls These data indicate that deficiency in ALDH2 activity may contribute to increased cisplatin sensitivity and cytotoxicity by producing more ROS by the treatment Based on these data, the amount of cisplatin used in patients may need to be adjusted based on their ALDH2 variant profile

Aldehyde dehydrogenase 2 activation and coevolution of its εPKC-mediated phosphorylation sites

Abstract: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a key enzyme for the metabolism of many toxic aldehydes such as acetaldehyde, derived from alcohol drinking, and 4HNE, an oxidative stress-derived lipid peroxidation aldehyde. Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (ePKC). Elevated ALDH2 is beneficial in reducing injury following myocardial infarction, stroke and other oxidative stress and aldehyde toxicity-related diseases. We have previously identified three ePKC phosphorylation sites, threonine 185 (T185), serine 279 (S279) and threonine 412 (T412), on ALDH2. Here we further characterized the role and contribution of each phosphorylation site to the enhancement of enzymatic activity by ePKC. Each individual phosphorylation site was mutated to a negatively charged amino acid, glutamate, to mimic a phosphorylation, or to a non-phosphorylatable amino acid, alanine. ALDH2 enzyme activities and protection against 4HNE inactivation were measured in the presence or absence of ePKC phosphorylation in vitro. Coevolution of ALDH2 and its ePKC phosphorylation sites was delineated by multiple sequence alignments among a diverse range of species and within the ALDH multigene family. We identified S279 as a critical ePKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by ePKC likely also protects the enzyme against reactive aldehydes. Finally, we demonstrate that the three ALDH2 phosphorylation sites co-evolved with ePKC over a wide range of species. Alignment of 18 human ALDH isozymes, indicates that T185 and S279 are unique ALDH2, ePKC specific phosphorylation sites, while T412 is found in other ALDH isozymes. We further identified three highly conserved serine/threonine residues (T384, T433 and S471) in all 18 ALDH isozymes that may play an important phosphorylation-mediated regulatory role in this important family of detoxifying enzymes. ePKC phosphorylation and its coevolution with ALDH2 play an important role in the regulation and protection of ALDH2 enzyme activity.

Genetic Polymorphisms of Alcohol Metabolizing Enzymes and Alcohol Consumption are Associated With Asymptomatic Cardiac Remodeling and Subclinical Systolic Dysfunction in Large Community-Dwelling Asians.

Abstract: Aims Excessive consumption of alcoholic beverages is associated with cardiac remodeling and cardiomyopathy. We examined the possible association of alcohol use, common Asian genetic variants in genes involved in alcohol metabolism, and cardiac structures/functions alterations. Methods A prospective, community-dwelling survey among individuals with available complete echocardiography examined the associations of alcohol use, cardiac structure/functions, and three common alcohol metabolizing genetic variants, including aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) and cytochrome P450 (CYP) isoform 2E1 (CYP2E1). Results Among 1577 participants (mean age: 53 ± 9, 59.7% female), we observed that in subjects with more frequent weekly ethanol intake showed greater left ventricle (LV) mass, more impaired diastolic functions, and reduced global longitudinal strain (GLS), systolic (SRs) and early diastolic strain rates (SRe) (P<0.05). After propensity matching for clinical confounders (n = 330:30 for frequent users and non-users), frequent alcohol use and subjects carrying ALDH2 (A/G or A/A), ADH1B (A/A) or CYP2E1(T/C or T/T) polymorphisms were all associated with worse GLSRs and GLSRe, with combined alcohol use and any given genetic variant aggravated these associations (all P < 0.05). Finally, we observed Gene-Gene synergistic effects on LV functional decline in frequent alcohol users by using linear mixed effect model (all interaction P < 0.05). Conclusions Among East Asians, even moderate alcohol consumption can confer subclinical adverse effects on cardiac systolic functions, which was most pronounced in subjects carrying common variants in alcohol metabolizing genes. These findings challenge the notion of beneficial influences of less heavy ethanol consumption on the heart, especially among East Asians. Short summary This study evaluated the association of level of alcohol consumption and genetic variants in genes involved in alcohol metabolism with changes in cardiac function in East Asians. Even moderate alcohol use conferred subclinical adverse effects on cardiac systolic functions, which were most pronounced in subjects carrying common alcohol metabolizing genes.

Thiophene bridged aldehydes (TBAs) image ALDH activity in cells via modulation of intramolecular charge transfer

Abstract: Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of an aldehyde to a carboxylic acid and are implicated in the etiology of numerous diseases. However, despite their importance, imaging ALDH activity in cells is challenging due to a lack of fluorescent imaging probes. In this report, we present a new family of fluorescent probes composed of an oligothiophene flanked by an aldehyde and an electron donor, termed thiophene-bridged aldehydes (TBAs), which can image ALDH activity in cells. The TBAs image ALDH activity via a fluorescence sensing mechanism based on the modulation of intramolecular charge transfer (ICT) and this enables the TBAs and their ALDH-mediated oxidized products, thiophene-bridged carboxylates (TBCs), to have distinguishable fluorescence spectra. Herein, we show that the TBAs can image ALDH activity in cells via fluorescence microscopy, flow cytometry, and in a plate reader. Using TBA we were able to develop a cell-based high throughput assay for ALDH inhibitors, for the first time, and screened a large, 1460-entry electrophile library against A549 cells. We identified α,β-substituted acrylamides as potent electrophile fragments that can inhibit ALDH activity in cells. These inhibitors sensitized drug-resistant glioblastoma cells to the FDA approved anti-cancer drug, temozolomide. The TBAs have the potential to make the analysis of ALDH activity in cells routinely possible given their ability to spectrally distinguish between an aldehyde and a carboxylic acid.

The roles of alcohol dehydrogenase in patients with atrial fibrillation

Abstract: Background Alcohol consumption is known to increase the risk of atrial fibrillation (AF). Whether the genotypes of alcohol-metabolizing genes (alcohol dehydrogenase [ADH1B]) are associated with the risk of AF recurrence after catheter ablation remains unclear. Methods and results The ADH1B genotypes of 281 patients who received catheter ablation for AF were examined. We followed this group of patients to monitor their AF recurrence. Alcohol consumption levels of this cohort were evaluated before and after catheter ablation. There was no difference in the underlying diseases presented by the patients with different ADH1B genotypes. Regardless of the ADH1B genotypes, the amount of alcohol consumption was the only factor associated with left atrial dilatation. The ADH1B*2 alleles (hazard ratio: ADH1B*1/*2 vs *1/*1: 2.64; ADH1B*2/*2 vs *1/*1: 1.80, P = 0.02) and the levels of alcohol consumption were independently associated with AF recurrence in the patients with paroxysmal AF after catheter ablation. ADH1B polymorphisms were not associated with AF recurrence in the patients with nonparoxysmal AF. We also found that the association of increased AF recurrence with alcohol consumption and the ADH1B genotypes cannot be explained by mechanisms of systemic inflammation. Conclusions ADH1B*2/*2 genotype and amount of alcohol consumption increase the risk of AF recurrence after catheter ablation.