The Anticancer Effect of a Novel Quinoline Derivative 91b1 through Downregulation of Lumican.

Quinoline derivatives have been reported to possess a wide range of pharmaceutical activities. Our group previously synthesized a series of quinoline compounds, in which compound 91b1 showed a significant anticancer effect. The purpose of this study was to evaluate the anticancer activity of compound 91b1 in vitro and in vivo, and screen out its regulated target. A series of cancer cell lines and nontumor cell lines were treated with compound 91b1 by MTS cytotoxicity assay and cell-cycle assay. In vivo anticancer activity was evaluated by a xenografted model on nude mice. Target prediction of 91b1 was assessed by microarray assay and confirmed by pancancer analysis. Relative expression of the target gene Lumican was measured by qRT-PCR. 91b1 significantly reduced tumor size in the nude mice xenograft model. Lumican was downregulated after 91b1 treatment. Lumican was proven to increase tumorigenesis in vivo, as well as cancer cell migration, invasion, and proliferation in vitro. The results of this study suggest that the anticancer activity of compound 91b1 probably works through downregulating the gene Lumican.

GAEC1 drives colon cancer progression.

Gene amplified in esophageal cancer 1 (GAEC1) expression and copy number changes are frequently associated with the pathogenesis of colorectal carcinomas. The current study aimed to identify the pathway and its transcriptional factors with which GAEC1 interacts within colorectal cancer, to gain a better understanding of the mechanics by which this gene exercises its effect on colorectal cancer. Two colonic adenocarcinoma cell lines (SW48 and SW480) and a nonneoplastic colon epithelial cell line (FHC) were transfected with GAEC1 to assess the oncogenic potential of GAEC1 overexpression. Multiple in vitro assays, including cell proliferation, wound healing, clonogenic, apoptosis, cell cycle, and extracellular flux, were performed. Western blot analysis was performed to identify potential gene-interaction partners of GAEC1 in vitro. Results showed that the overexpression of GAEC1 significantly increased cell proliferation, migration, and clonogenic potential ( P < 0.05) of colonic adenocarcinoma. Furthermore, GAEC1 portrayed its ability to influence mitochondrial respiration changes. The observations were in tandem with a significant increase in the expression of phosphorylated protein kinase B, forkhead box O3, and matrix metallopeptidase 9. Thus, GAEC1 has a role in regulating gene pathways, potentially in the Akt pathway. This could help in developing targeted therapies in the future.

The design, synthesis and evaluation of selenium-containing 4-anilinoquinazoline hybrids as anticancer agents and a study of their mechanism.

Inhibition of tubulin polymerization is one of the significant strategies in the treatment of cancer. Inspired by the excellent antitumor activity of EP128495 and the beneficial biological activities of selenium compounds, a series of new selenium-containing 4-anilinoquinazoline hybrids were synthesized and evaluated as tubulin polymerization inhibitors. An anti-proliferative activity assay showed that most of the compounds inhibited human sensitive cancer cells at low nanomolar concentrations. A mechanism study revealed that the optimal compound 5a disrupted microtubule dynamics, decreased the mitochondrial membrane potential and arrested HeLa cells in the G2/M phase, finally resulting in cellular apoptosis.

Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive disease characterized by frequent deletions on 6q, and constitutive activation of signal transducer and activator of transcription 3 (STAT3). Phosphorylation at Tyr705 activates STAT3, inducing dimerization, nuclear translocation, and DNA binding. In this study, we investigated whether receptor-type tyrosine-protein phosphatase κ (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3-specifying motif, negatively regulates STAT3 activation in NKTCL. PTPRK was highly expressed in normal NK cells but was underexpressed in 4 of 5 (80%) NKTCL cell lines and 15 of 27 (55.6%) primary tumors. Significantly, PTPRK protein expression was inversely correlated with nuclear phospho-STAT3(Tyr705) expression in NKTCL cell lines (P = .025) and tumors (P = .040). PTPRK restoration decreased nuclear phospho-STAT3(Tyr705) levels, whereas knockdown of PTPRK increased such levels in NKTCL cells. Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). Restoration of PTPRK inhibited tumor cell growth and reduced the migration and invasion ability of NKTCL cells. Monoallelic deletion and promoter hypermethylation caused underexpression of PTPRK messenger RNA in NKTCL, and methylation of the PTPRK promoter significantly correlated with inferior overall survival (P = .049) in NKTCL patients treated with the steroid-dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide regimen. Altogether, our findings show that PTPRK underexpression leads to STAT3 activation and contributes to NKTCL pathogenesis.

Overexpression of microRNA-1288 in oesophageal squamous cell carcinoma.

PURPOSE: This study aims to examine the expression profiles miR-1288 in oesophageal squamous cell carcinoma (ESCC). The cellular implications and target interactions of ESCC cells following miR-1288 overexpression was also examined. METHODS: In total, 120 oesophageal tissues (90 primary ESCCs and 30 non-neoplastic tissues) were recruited for miR-1288 expression analysis using qRT-PCR. An exogenous miR-1288 mimic and its inhibitor were used to explore the in-vitro effects of miR-1288 on ESCC cells by performing cell proliferation, colony formation, cell invasion and migration assays. Localisation and modulatory changes of various miR-1288 regulated proteins such as FOXO1, p53, TAB3, BCL2 and kRAS was examined using immunofluorescence and western blot. RESULTS: Overexpression of miR-1288 was more often noted in ESCC tissues when compared to non-neoplastic oesophageal tissues. High expression was often noted in high grade carcinomas and with metastases. Patients with high levels of miR-1288 expression showed a slightly better survival compared to patients with low miR-1288 levels. Furthermore, overexpression of miR-1288 showed increased cell proliferation and colony formation, improved cell migration and enhanced cell invasion properties in ESCC cells. In addition, miR-1288 overexpression in ESCC cells showed repression of cytoplasmic tumour suppressor FOXO1 protein expression. Inversely, inhibition of miR-1288 expression exhibited remarkable upregulation of FOXO1 protein, while expressions of other tested proteins remain unchanged. CONCLUSIONS: Up regulation of miR-1288 expression in ESCC tissues and miR-1288 induced oncogenic features of ESCC cells in-vitro indicates the oncogenic roles of miR-1288 in ESCCs. Overexpression of miR-1288 play a key role in the pathogenesis of ESCCs and its modulation may have potential therapeutic value in patients with ESCC.

Corticosteroid implants for chronic non-infectious uveitis.

BACKGROUND: Uveitis is a term used to describe a heterogeneous group of intraocular inflammatory diseases of the anterior, intermediate, and posterior uveal tract (iris, ciliary body, choroid). Uveitis is the fifth most common cause of vision loss in high-income countries, accounting for 5% to 20% of legal blindness, with the highest incidence of disease in the working-age population.Corticosteroids are the mainstay of acute treatment for all anatomical subtypes of non-infectious uveitis and can be administered orally, topically with drops or ointments, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation. OBJECTIVES: To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 15 April 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for studies. We last searched the electronic databases on 6 November 2015.We also searched reference lists of included study reports, citation databases, and abstracts and clinical study presentations from professional meetings. SELECTION CRITERIA: We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone intravitreal implants with standard-of-care therapy with at least six months of follow-up after treatment. We included studies that enrolled participants of all ages who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for inclusion. Two review authors independently extracted data and assessed the risk of bias for each study. MAIN RESULTS: We included data from two studies (619 eyes of 401 participants) that compared FA implants with standard-of-care therapy. Both studies used similar standard-of-care therapy that included administration of prednisolone and, if needed, immunosuppressive agents. The studies included participants from Australia, France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, the United Kingdom, and the United States. We assessed both studies at high risk of performance and detection bias.Only one study reported our primary outcome, recurrence of uveitis at any point during the study through 24 months. The evidence, judged as moderate-quality, showed that a FA implant probably prevents recurrence of uveitis compared with standard-of-care therapy (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.14 to 0.59; 132 eyes). Both studies reported safety outcomes, and moderate-quality evidence showed increased risks of needing cataract surgery (RR 2.98, 95% CI 2.33 to 3.79; 371 eyes) and surgery to lower intraocular pressure (RR 7.48, 95% CI 3.94 to 14.19; 599 eyes) in the implant group compared with standard-of-care therapy through two years of follow-up. No studies compared dexamethasone implants with standard-of-care therapy. AUTHORS' CONCLUSIONS: After considering both benefits and harms reported from two studies in which corticosteroids implants were compared with standard-of-care therapy, we are unable to conclude that the implants are superior to traditional systemic therapy for the treatment of non-infectious uveitis. These studies exhibited heterogeneity in design and outcomes that measured efficacy. Pooled findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and high intraocular pressure compared with standard-of-care therapy.

Preparation of 8-hydroxyquinoline derivatives as potential antibiotics against Staphylococcus aureus.

This work describes the preparation of quinoline compounds as possible anti-bacterial agents. The synthesized quinoline derivatives show anti-bacterial activity towards Staphylococcus aureus. It is interesting to observe that the synthetic 5,7-dibromo-2-methylquinolin-8-ol (4) shows a similar minimum inhibitory concentration of 6.25µg/mL as compared to that of methicillin (3.125µg/mL) against Staphylococcus aureus.

The puzzling issue of 'vehicle-treated control' when using ethanol as drug carrier for MCF-7 cells.

Ethanol has been commonly used as a vehicle for drug discovery purpose in vitro. The human breast cancer MCF-7 estrogen dependent cell line is a common in vitro model used for hormonal therapy study. However, special precaution is suggested when ethanol is used in pharmacological tests as solvent in order to evaluate the biological activity of potential drugs especially concerning about the MCF-7. Ethanol was shown to stimulate the proliferation of this estrogen receptor positive cell line. Here, we have further demonstrated that the dose responsive stimulatory effect of ethanol on the MCF-7 cells after pre-incubating the breast carcinoma cells with phenol red-free medium and stripped fetal bovine serum. Our findings open a discussion for the evaluation of ethanol as solvent for drug discovery and screening when using MCF-7 cells as a testing model.

In vivo antitumour activity of amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B.

We explore the possible cellular cytotoxic activity of an amphiphilic silicon(IV) phthalocyanine with axially ligated rhodamine B under ambient light experimental environment as well as its in vivo antitumour potential using Hep3B hepatoma cell model. After loading into the Hep3B hepatoma cells, induction of cellular cytotoxicity and cell cycle arrest were detected. Strong growth inhibition of tumour xenograft together with significant tumour necrosis and limited toxicological effects exerted on the nude mice could be identified.

Toll-like receptor 3 is required for development of retinopathy caused by impaired all-trans-retinal clearance in mice.

Chronic inflammation is an important component that contributes to many age-related neurodegenerative diseases, including macular degeneration. Here, we report a role for toll-like receptor 3 (TLR3) in cone-rod dystrophy (CORD) of mice lacking ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8), proteins critical for all-trans-retinal clearance in the retina. Increased expression of toll-like receptor-signaling elements and inflammatory changes were observed in Rdh8(-/-)Abca4(-/-) eyes by RNA expression analysis. Unlike 3-month-old Rdh8(-/-)Abca4(-/-) mice that developed CORD, 6-month-old Tlr3(-/-)Rdh8(-/-)Abca4(-/-) mice did not evidence an abnormal retinal phenotype. Light-induced retinal degeneration in Tlr3(-/-)Rdh8(-/-)Abca4(-/-) mice was milder than that in Rdh8(-/-)Abca4(-/-) mice, and a 2-fold increased TLR3 expression was detected in light-illuminated retinas of Rdh8(-/-)Abca4(-/-) mice compared with nonilluminated retinas. Poly(I-C), a TLR3 ligand, caused caspase-8-independent cellular apoptosis. Whereas poly(I-C) induced retinal cell death in Rdh8(-/-)Abca4(-/-) and WT mice both in vivo and ex vivo, this was not seen in mice lacking Tlr3. Far fewer invasive macrophage/microglial cells in the subretinal space and weaker activation of Muller glial cells were exhibited by Tlr3(-/-)Rdh8(-/-) Abca4(-/-) mice compared with Rdh8(-/-)Abca4(-/-) mice at 3 and 6 months of age, indicating that loss of TLR3 inhibits local inflammation in the retina. Both poly(I-C) and endogenous products emanating from dying/dead retinal cells induced NF-κB and IRF3 activation. These findings demonstrate that endogenous products from degenerating retina stimulate TLR3 that causes cellular apoptosis and retinal inflammation and that loss of TLR3 protects mice from CORD.

Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light-induced damage.

All-trans-retinal and its condensation-products can cause retinal degeneration in a light-dependent manner and contribute to the pathogenesis of human macular diseases such as Stargardt's disease and age-related macular degeneration. Although these toxic retinoid by-products originate from rod and cone photoreceptor cells, the contribution of each cell type to light-induced retinal degeneration is unknown. In this study, the primary objective was to learn whether rods or cones are more susceptible to light-induced, all-trans-retinal-mediated damage. Previously, we reported that mice lacking enzymes that clear all-trans-retinal from the retina, ATP-binding cassette transporter 4 and retinol dehydrogenase 8, manifested light-induced retinal dystrophy. We first examined early-stage age-related macular degeneration patients and found retinal degenerative changes in rod-rich rather than cone-rich regions of the macula. We then evaluated transgenic mice with rod-only and cone-like-only retinas in addition to progenies of such mice inbred with Rdh8(-/-) Abca4(-/-) mice. Of all these strains, Rdh8(-/-) Abca4(-/-) mice with a mixed rod-cone population showed the most severe retinal degeneration under regular cyclic light conditions. Intense light exposure induced acute retinal damage in Rdh8(-/-) Abca4(-/-) and rod-only mice but not cone-like-only mice. These findings suggest that progression of retinal degeneration in Rdh8(-/-) Abca4(-/-) mice is affected by differential vulnerability of rods and cones to light.

Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype.

Suppressive effects of DUSP6 in tumorigenesis and EMT-associated properties were observed. Dual-specificity phosphatase (DUSP6) is a MAP kinase phosphatase (MKP) negatively regulating the activity of ERK, one of the major molecular switches in the MAPK signaling cascade propagating the signaling responses during malignancies. The impact of DUSP6 in EMT and its contribution to tumor dissemination has not yet been characterized. Due to differences in tumor microenvironments affecting cell signaling during cancer progression, DUSP6 may play varying roles in tumor development. We sought to examine the potential role of DUSP6-mediated tumorigenesis and EMT-associated properties in two aerodigestive tract cancers, namely, esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). Significant loss of DUSP6 was observed in 100% of 11 ESCC cell lines and 71% of seven NPC cell lines. DUSP6 expression was down-regulated in 40% of 30 ESCC tumor tissues and 75% of 20 NPC tumor tissues compared to their respective normal counterparts. Suppressive effects of DUSP6 in tumor formation and cancer cell mobility are seen in in vivo tumorigenicity assay and in vitro colony formation, three-dimensional Matrigel culture, cell migration and invasion chamber tests. Notably, overexpression of DUSP6 impairs EMT-associated properties. Furthermore, tissue microarray analysis reveals a clinical association of DUSP6 expression with better patient survival. Taken together, our study provides a novel insight into understanding the functional impact of DUSP6 in tumorigenesis and metastasis of ESCC and NPC.

Development of phyllanthin containing microcapsules and their improved biological activity towards skin cells and Staphylococcus aureus.

Chitosan based microcapsule which encapsulated with phyllanthin was developed by simple coacervation. The composition and surface morphology of phyllanthin containing microcapsules were analyzed by Fourier Transform Infrared spectroscopy and Scanning Electron Microscopy, respectively. The release of phyllanthin from the microcapsules was found to be more than 60% after 120 h. In vitro biological assays demonstrated that these phyllanthin containing microcapsules showed a stronger anti-oxidation potential on both human fibroblasts and keratinocytes as well as a better growth inhibitory activity towards Staphylococcus aureus.

Cytoplasmic Forkhead box M1 (FoxM1) in esophageal squamous cell carcinoma significantly correlates with pathological disease stage.

UNLABELLED: Esophageal cancer is a deadly cancer with esophageal squamous cell carcinoma (ESCC) as the major type. Until now there has been a lack of reliable prognostic markers for this malignancy. This study aims to investigate the clinical correlation between Forkhead box M1 (FoxM1)and patients' parameters in ESCC. METHODS: Immunohistochemistry was performed to investigate the expression and localization of FoxM1 in 64ESCC tissues and 10 nontumor esophageal tissues randomly selected from 64 patients before these data were used for clinical correlations. RESULTS: Cytoplasmic and nuclear expressions of FoxM1 were found in 63 and 16 of the 64 ESCC tissues, respectively.Low cytoplasmic expression of FoxM1 was correlated with early pathological stage in ESCC (P = 0.018),while patients with nuclear FoxM1 were younger in age than those without nuclear expression (P\0.001).Upregulation of FoxM1 mRNA was found in five ESCCcell lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4,and SLMT-1) when compared to non-neoplastic esophageal squamous cell line NE-1 using quantitative polymerase chain reaction (qPCR). Except for HKESC-3, all studied ESCC cell lines demonstrated a high expression of FoxM1 protein using immunoblot. A high mRNA level of FoxM1 was observed in all of the ESCC tissues examined when compared to their adjacent nontumor tissues using qPCR. CONCLUSION: Cytoplasmic FoxM1 was correlated with pathological stage and might be a biomarker for advanced ESCC.

Chimeric antigen receptor T cells applied to solid tumors.

Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.

The ECM protein LTBP-2 is a suppressor of esophageal squamous cell carcinoma tumor formation but higher tumor expression associates with poor patient outcome.

Our previous studies of chromosome 14 transfer into tumorigenic esophageal squamous cell carcinoma (ESCC) cell line, SLMT, suggested the existence of tumor suppressor genes on chromosome 14. Gene expression profiling of microcell hybrids and the tumor segregants identified an interesting gene, LTBP-2 (latent transforming growth factor ß binding protein 2), which has been analyzed here for its role in ESCC. LTBP-2 maps to 14q24 and encodes a secreted protein, which is a component of the extracellular matrix microfibrils. LTBP-2 expression was downregulated in ESCC cell lines and tumor tissues. Promoter hypermethylation was found to be involved in LTBP-2 inactivation. Functional studies indicated its tumor-suppressive roles in ESCC. In the in vitro colony formation and Matrigel three-dimensional culture assays, LTBP-2 decreased the colony-forming abilities of ESCC cell lines. LTBP-2 expression was associated with reduction of cell migrating and invasive abilities. LTBP-2 could also reduce the tube-forming ability of endothelial cells. Moreover, LTBP-2 induced tumor suppression in in vivo nude mouse assays. Tissue microarray immunohistochemical staining analysis indicated that LTBP-2 expression is reduced in tumor tissues when compared to normal tissues, and LTBP-2 expression correlated significantly with the survival of ESCC patients. Thus, LTBP-2 appears to play an important role in ESCC.

Republished review: Ocular manifestations of the antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a heterogenous group of antibodies directed against negatively charged phospholipids including antiphospholipid antibodies (aPL), anticardiolipin antibodies (aCL) and ß-2 glycoprotein I (aß-2-GP1). The major features of this disorder include arterial and venous thrombosis and recurrent fetal loss. The vasculature of the eye is frequently involved and may be the presenting manifestation. A diagnosis of APS should be considered in a young patients without traditional thromboembolic risk factors presenting with ocular vaso-occlusive disease. Management of these patients involves a team-approach with a haematologist/oncologist or rheumatologist to manage the coagulation status of these patients to prevent further systemic vascular occlusions.

Patient-Derived Xenograft and Mice Models in Esophageal Squamous Cell Carcinoma.

Mouse models are important in the study of pathogenesis, testing new treatment, and monitoring the progress of treatment in patients with esophageal squamous cell carcinoma (ESCC). The mice commonly used are immunosuppressed. The first category of models is for basic research and includes genetically engineered mouse models and carcinogen- or diet-induced mouse models. The second category of models involves either injection of cells with altered gene function related to pathogenesis of ESCC or ESCC cell lines. This method is commonly used and relatively inexpensive and simple to use. These cells commonly being subcutaneous injected in flank (subcutaneous xenograft model), tail vein, or peritoneum of immunodeficient mice. Direct implantation into the esophagus (orthotopic xenograft model) is also performed despite the cost and technical difficulties. The third category of mouse model is the patient-derived xenograft (PDX) model. In this model, ESCC tissues (instead of cell lines) removed from the patient are implanted into immunodeficient mice. This model appears promising for personalized medicine and of high resemblance to the nature of human ESCC, but there are many limitations for the use. It is likely to be used more in research in ESCC in the future. In this chapter, we detailed the preparation and experiments of PDX model from a patient with ESCC.

Monochromosome transfer and microarray analysis identify a critical tumor-suppressive region mapping to chromosome 13q14 and THSD1 in esophageal carcinoma.

Loss of chromosome 13q regions in esophageal squamous cell carcinoma (ESCC) is a frequent event. Monochromosome transfer approaches provide direct functional evidence for tumor suppression by chromosome 13 in SLMT-1, an ESCC cell line, and identify critical regions at 13q12.3, 13q14.11, and 13q14.3. Differential gene expression profiles of three tumor-suppressing microcell hybrids (MCH) and their tumorigenic parental SLMT-1 cell line were revealed by competitive hybridization using 19k cDNA oligonucleotide microarrays. Nine candidate 13q14 tumor-suppressor genes (TSG), including RB1, showed down-regulation in SLMT-1, compared with NE1, an immortalized normal esophageal epithelial cell line; their average gene expression was restored in MCHs compared with SLMT-1. Reverse transcription-PCR validated gene expression levels in MCHs and a panel of ESCC cell lines. Results suggest that the tumor-suppressing effect is not attributed to RB1, but instead likely involves thrombospondin type I domain-containing 1 (THSD1), a novel candidate TSG mapping to 13q14. Quantitative reverse transcription-PCR detected down-regulation of THSD1 expression in 100% of ESCC and other cancer cell lines. Mechanisms for THSD1 silencing in ESCC involved loss of heterozygosity and promoter hypermethylation, as analyzed by methylation-specific PCR and clonal bisulfite sequencing. Transfection of wild-type THSD1 into SLMT-1 resulted in significant reduction of colony-forming ability, hence providing functional evidence for its growth-suppressive activity. These findings suggest that THSD1 is a good candidate TSG.

The preparation of 2,6-disubstituted pyridinyl phosphine oxides as novel anti-cancer agents.

A series of 2,6-dimethoxylpyridinyl phosphine oxides have been synthesized and examined for their antitumor activity. 2,6-Dimethoxy-3-phenyl-4-diphenylphosphinoylpyridine 2 has been employed as the lead compound for this study. We found out that the presence of phosphine oxide on the 2,6-dimethoxylpyridine ring is important for the antitumor activity; the presence of bromine on this core leads to a further enhancement of its antitumor activity. This is the first reported work on the antitumor activity of the 2,6-dimethoxy-3,5-dibromopyridinyl phosphine oxide 5b towards MDAMB-231 breast cancer and SKHep-1 hepatoma cell lines.