Arsenic trioxide suppresses tumour growth in squamous cell lung carcinoma

This journal suppl. entitled: 20th Medical Research Conference; Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong KongINTRODUCTION: Squamous cell lung carcinoma (SCC) belongs to the second most common subtype in non–small-cell lung carcinoma. Recently, doublet chemotherapy regimens remain the cornerstone of first-line systemic treatment. Therefore, new therapeutic approach is urgently needed. Arsenic trioxide (ATO) is a traditional Chinese medicine which has multiple anti-cancer mechanisms including apoptosis. ATO has been used clinically in acute promyelocytic leukaemia. ATO has been shown to induce apoptosis in lung adenocarcinoma …published_or_final_versio

Massive degradation in FGFR/Akt/Erk signaling by arsenic trioxide and FGFR inhibitor PD173074 in squamous cell lung carcinoma SK-MES-1

This journal suppl. entitled: 20th Medical Research Conference; Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong KongINTRODUCTION: Lung cancer is the top cancer killer. Squamous cell carcinoma (SCC) represents the second most common histological subtype of lung cancer. Arsenic trioxide (ATO) has been demonstrated to inhibit tumour growth in lung adenocarcinoma and initiate apoptosis in acute promyelocytic leukaemia. Fibroblast growth factor (FGF) receptor (FGFR) amplification is shown in some SCC. FGFR inhibitor (eg PD173074) has been …published_or_final_versio

E2F1 Downregulation by Arsenic Trioxide in Lung Adenocarcinoma

Lung cancer is one of the most common cancers worldwide. Arsenic trioxide (ATO) has been approved by the U.S. Food and Drug Administration for the treatment of acute promyelocytic leukemia. Nonetheless preliminary data have suggested potential activity of ATO in solid tumors including lung cancer. This study aimed to examine the underlying mechanisms of ATO in the treatment of lung adenocarcinoma. Using a panel of 7 lung adenocarcinoma cell lines, the effects of ATO treatment on cell viability, expression of E2F1 and its downstream targets, phosphatidylserine externalization, mitochondrial membrane depolarization and alteration of apoptotic/anti-apoptotic factors were studied. Tumor growth inhibition in vivo was investigated using a nude mouse xenograft model. ATO decreased cell viability with clinically achievable concentrations (8 uM) in all cell lines investigated. This was accompanied by reduced expression of E2F1, cyclin A2, skp2, c-myc, thymidine kinase and ribonucleotide reductase M1, while p-c-Jun was upregulated. Cell viability was significantly decreased with E2F1 knockdown. Treatment with ATO resulted in phosphatidylserine externalization in H23 cells and mitochondrial membrane depolarization in all cell lines, associated with truncation of Bid, downregulation of Bcl-2, upregulation of Bax and Bak, caspase-9 and caspase-3 activation and PARP cleavage. Using a H358 xenograft model, the tumor growth was suppressed in the ATO treatment group during 8 days of treatment, associated with downregulation of E2F1 and upregulation of truncated Bid and cleaved caspase-3. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, partially mediated through E2F1 downregulation and apoptosis.published_or_final_versio

Infant growth during the first year of life and age at puberty onset: Hong Kong’s "Children of 1997" birth cohort

published_or_final_version6th World Congress on Developmental Origins of Health and Disease, Santiago, Chile, 19 - 22 November 2009. In Journal of Developmental Origins of Health and Disease, 2009, v. 1 n. S1, p. S13

Developing a platform of environmental omics for the green-lipped mussel Perna viridis

Session Track: Aquatic and terrestrial ecotoxicologyOral presentationConference Theme: Science across bridges, borders and boundariesThe green-lipped mussel Perna viridis is an important marine biomonitor species in pollution monitoring and ecotoxicological studies in Asia-Pacific region, and considered as a subtropical equivalent biomonitor of the temperate Mytilus species. However, the genomic information of P. viridis is still largely unexplored when compared with Mytilus species. This study aimed to establish a transcriptomic profile of P. viridis using the next generation sequencing technology and provide a good representative set of genomic information for elucidation of toxic mechanisms upon pollution stresses and identification of a suite of suitable biomarkers for monitoring marine pollution and environmental stresses. To obtain a wide spectrum of environmental-associated transcripts, adult mussels (4-5 cm shell length) were collected from different locations in Hong Kong and from those after 24-hour exposures to various challenges of physical stresses and chemical pollutants, so as to cover a wide range of stress-associated transcription patterns for future environmental studies. Two males and females from each location and from each treatment were chosen for obtaining the three target tissues (i.e., hepatopancreas, gill and adductor muscle). For each sex and each tissue type, a total RNA sample was extracted from pooled tissues from the field and laboratory treated mussels. The RNA sample was subjected to cDNA library construction, followed by the RNA-sequencing using a Solexa GAIIx (Illumina). Including the splicing variants, a de novo assembly of a total length of 295,064,579 base-pair (bp) contig was obtained, with 233,257 contigs assembled of an average size of 1264 bp. The 192,879 non-redundant assembled transcripts were blasted against the NCBI nr database and three molluscan EST databases, and resulted in 44,713 transcripts with at least a blast hit, and having a top match with the sequences from the Pacific oyster, Crassostrea gigas (27,651 transcripts). A total of 5,131 transcripts were assigned with KEGG annotation involving in 329 pathways. Based on multivariate statistical analysis, expression patterns of genes from stress associated responses and detoxification were strongly tissue-specific but the differences between genders were little. The anticipated genomic database generated from this study will further strengthen the role of P. viridis as a universal marine biomonitor in the Asia-Pacific region.published_or_final_versio

IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-kB activation

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.published_or_final_versio

The Role of Dairy Products and Milk in Adolescent Obesity: Evidence from Hong Kong's "Children of 1997" Birth Cohort

Background: Observational studies, mainly from Western populations, suggest dairy consumption is inversely associated with adiposity. However, in these populations the intake range is limited and both diet and obesity may share social patterning. Evidence from non-Western developed settings with different social patterning, is valuable in distinguishing whether observed associations are biologically mediated or socially confounded. Objective: To examine the associations of milk or other dairy product consumption with adolescent obesity. Methods: We used multivariable linear regression models to examine the associations of milk or other dairy product consumption, obtained from a food frequency questionnaire, at 11 years with body mass index (BMI) z-scores at 13 years and waist hip ratio (WHR) at 11 years, in 5,968 adolescents from a Chinese birth cohort, comprising 88% of births in April and May 1997. We used multiple imputation for missing exposures and confounders. Results: Only 65.7% regularly consumed milk and 72.4% other dairy products. Milk and other dairy product consumption was positively associated with socio-economic position but not with BMI z-score or WHR, with or without adjustment for sex, mother's birthplace, parental education, physical activity and other food consumption. Conclusions: The lack of association of milk and other dairy product consumption with adiposity in a non-Western setting was not consistent with the majority of evidence from Western settings. Observed anti-obesigenic effects in Western settings may be due to socially patterned confounding. © 2012 Lin et al.published_or_final_versio

Growth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts

BACKGROUND: Malignant pleural mesothelioma (MPM) is a difficult-to-treat global disease. Pegylated arginase (BCT-100) has recently shown anti-tumor effects in hepatocellular carcinoma, acute myeloid leukemia and melanoma. This study aims to investigate the effects of PEG-BCT-100 in MPM. METHODS: A panel of 5 mesothelioma cell lines (H28, 211H, H226, H2052 and H2452) was used to study the in vitro effects of BCT-100 by crystal violet staining. The in vivo effects of BCT-100 were studied using 211H and H226 nude mice xenografts. Protein expression (argininosuccinate synthetase, ornithine transcarbamylase, cleaved PARP, cleaved caspase 3, cyclins (A2, D3, E1 and H), CDK4 and Ki67) and arginine concentration were evaluated by Western blot and ELISA respectively. Cellular localization of BCT-100 was detected by immunohistochemistry and immunoflorescence. TUNEL assay was used to identify cellular apoptotic events. RESULTS: Argininosuccinate synthetase was expressed in H28, H226, and H2452 cells as well as 211H and H266 xenografts. Ornithine transcarbamylase was undetectable in all cell lines and xenograft models. BCT-100 reduced in vitro cell viability (IC50 values at 13-24 mU/ml, 72 h) across different cell lines and suppressed tumor growth in both 211H and H226 xenograft models. BCT-100 (60 mg/kg) significantly suppressed tumor growth (p < 0.01) with prolonged median survival (p < 0.01) in both xenograft models. Combining BCT-100 with pemetrexed or cisplatin conferred no additional benefits over single agents. Serum and intratumoral arginine levels were effectively decreased by BCT-100, associated with cytosolic accumulation of BCT-100 within tumor cells. Apoptosis (PARP cleavage in 211H xenografts; Bcl-2 downregulation, and cleavage of PARP and caspase 3 in H226 xenografts; positive TUNEL staining in both) and G1 arrest (downregulation of cyclin A2, D3, E1 and CDK4 in 211H xenografts; suppression of cyclin A2, E1, H and CDK4 in H226 xenografts) were evident with BCT-100 treatment. Furthermore, proliferative factor Ki67 was downregulated in BCT-100 treatments arms. CONCLUSIONS: BCT-100 suppressed tumor growth with prolonged median survival partially mediated by intratumoral arginine depletion resulting in apoptosis and G1 arrest in mesothelioma xenograft models. The findings provide scientific evidence to support further clinical development of BCT-100 in treatment of MPM.published_or_final_versio

De novo transcriptome analysis of Perna viridis highlights tissue-specific patterns for environmental studies

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Tumour Growth-Suppressive Effect of Arsenic Trioxide in Squamous Cell Lung Carcinoma

Squamous cell lung carcinoma (SCC) is the second commonest subtype of non-small cell lung carcinoma. The anticancer effects of arsenic trioxide (ATO) in lung adenocarcinoma and small cell lung carcinoma have been reported while in SCC are unknown. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Western blot were used to determine cell viability and protein expression respectively. Phosphatidylserine externalization, mitochondrial membrane depolarization and cell cycle distribution were studied using flow cytometry. The in vivo effect of ATO was investigated with a xenograft model. SK-MES-1 and SW900 SCC cells were sensitive to clinically relevant concentrations of ATO. ATO induced apoptosis, mitochondrial membrane depolarization, G2/M arrest, downregulation of XIAP, Bcl-2, E2F1, thymidylate synthase and RRM1 as well as upregulation of Bak, cleaved PARP and cleaved caspase 3 in a cell-line specific manner. In SW900 xenograft model, tumour growth was inhibited by ATO with formation of apoptotic bodies and downregulation of Bcl-2 and E2F1. In conclusion, ATO suppressed growth of SCC in vitro and in vivo.published_or_final_versio