Biomedical subjects

L G Wang

Publications and source records attributed to L G Wang.

At least 19 recordsLinked to original sources

PubMed2007

Dual action on promoter demethylation and chromatin by an isothiocyanate restored GSTP1 silenced in prostate cancer.

Prostate carcinoma is characterized by the silencing of pi-class glutathione S-transferase gene (GSTP1), which encodes a detoxifying enzyme. The silencing of GSTP1, due to aberrant methylation at the CpG island in the promoter/5'-UTR, occurs in the vast majority of prostate tumors and precancerous lesions. It is a pathologic marker and probably an underlying cause of oxidative damage and inflammation at tumor initiation. Inhibition of the aberrant promoter methylation could therefore be an effective mean to prevent carcinogenesis. Several isothiocyanates, including phenethyl isothiocyanate (PEITC), found naturally in cruciferous vegetables, induced growth arrest and apoptosis in prostate cancer cells in culture and xenografts. The effects of PEITC to reactivate GSTP1 were investigated. Exposure of prostate cancer LNCaP cells to PEITC inhibited the activity and level of histone deacetylases (HDACs), and induced selective histone acetylation and methylation for chromatin unfolding. Concurrently PEITC demethylated the promoter and restored the unmethylated GSTP1 in both androgen-dependent and -independent LNCaP cancer cells to the level found in normal prostatic cells, as quantified by methylation-specific PCR and pyrosequencing. The dual action of PEITC on both the DNA and chromatin was more effective than 5'-Aza-2'-deoxycytidine, sodium butyrate, or trichostatin A (TSA), and may de-repress the methyl-binding domain (MBD) on gene transcription. The PEITC-mediated cross-talk between the DNA and chromatin in demethylating and reactivating GSTP1 genes, which is critically inactivated in prostate carcinogenesis, underlines a primary mechanism of cancer chemoprevention. Consequently, new approaches could be developed, with isothiocyanates to prevent and inhibit malignancies.

Acetylation↗

PubMed2006

Repression of androgen receptor in prostate cancer cells by phenethyl isothiocyanate.

BACKGROUND: Prostate cancer usually progresses to androgen refractory after an initial anti-androgen treatment. The androgen receptor (AR) is a pivotal factor for the androgen-mediated growth and maintenance of the prostate. Abnormality of the AR, such as overexpression has been postulated to be related to the hormone independent growth of the cancer. Although we previously demonstrated that the AR expression could be modulated by isothiocyanates, which are natural constituents of cruciferous vegetables, the mechanism, however, remained to be clarified. We have since investigated the mechanism of phenethyl isothiocyanate (PEITC) in AR regulation. METHODS: A human androgen dependent prostate cancer cell line LNCaP (AD) and its sub-line LNCaP (AI), i.e. androgen independent but overexpressing AR, were exposed to PEITC. The effects of PEITC on cell growth and AR expression/transcription were analyzed with MTT assay, real-time PCR and western blotting. The AR promoter activity was analyzed with the reporter activity after transfection with pAR-luc. The effects on Sp1, the major transcription factor of the AR, were tested with Sp1-luc activity, western blotting and electrophoretic mobility shift assay. RESULTS: PEITC induced a significant growth inhibition, with equal IC(50), in both AD and AI cells. The AR present in both cells was repressed as demonstrated with real-time PCR and western blot. PEITC mediates dual effects at transcriptional and post-translational levels to regulate the AR. At transcriptional level the AR level was reduced via inhibition of the transcription factor Sp1, and at post-translational level by accelerating protein degradation. CONCLUSION: PEITC represses AR transcription and expression, and mediates growth arrest in androgen dependent and independent prostate cancer cells. With the AR modulation and growth attenuation, PEITC and possibly other isothiocyanates, may prevent and inhibit hormone sensitive and refractory prostate cancer.

Androgen Receptor Antagonists↗

PubMed2003

Unique induction of p21(WAF1/CIP1)expression by vinorelbine in androgen-independent prostate cancer cells.

To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21(WAFl/CIP1) (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

Androgen Antagonists↗

PubMed2003

Cluster-doping approach for wide-gap semiconductors: the case of p-type ZnO.

First-principles calculations on p-type doping of the paradigm wide-gap ZnO semiconductor reveal that successful doping depends much on engineering a stable local chemical bonding environment. We suggest a cluster-doping approach in which a locally stable chemical environment is realized by using few dopant species. We explain two puzzling experimental observations, i.e., that monodoping N in ZnO via N2 fails to produce p-type behavior, whereas using an NO source produces metastable p-type behavior, which disappears over time.

Journal Article↗

PubMed2003

Adaptive crystal structures: CuAu and NiPt.

We discover that Au-rich Cu1-xAux and Pt-rich Ni1-xPtx contain a composition range in which there is a quasicontinuum of stable, ordered "adaptive structures" made of (001) repeat units of simple structural motifs. This is found by searching approximately 3x10(6) different fcc configurations whose energies are parametrized via a "cluster expansion" of first-principles-calculated total energies of just a few structures. This structural adaptivity is explained in terms of an anisotropic, long-range strain energy.

Journal Article↗

PubMed2002

The role of the nanoscale in surface reactions: CO2 on CdSe.

Cd-rich CdSe nanocrystals below a critical size, under illumination, catalyze CO2 fixation, but bulk CdSe surfaces do not. We report first-principles calculations in which we determine the roles of faceting, deviations from stoichiometry, photoexcitation, and electron confinement, and the specific physics of the nanoscale. We further establish that catalysis does not occur at the nanocrystal surface; instead, neutral molecules adsorb, desorb negatively charged, and react elsewhere. Finally, we predict that n-type doped CdSe nanocrystals would be effective catalysts without photoexcitation.

Journal Article↗

PubMed2001

Differential effect of vinorelbine versus paclitaxel on ERK2 kinase activity during apoptosis in MCF-7 cells.

The effects of vinorelbine and paclitaxel on the activity of extracellular signal-regulated protein kinase2 (ERK2), a member of MAP kinase, and its role in the induction of bcl-2 phosphorylation and apoptosis were evaluated in MCF-7 cells. We demonstrated that ERK2 was activated rapidly by vinorelbine, and was inhibited by either paclitaxel or estramustine. A 3-fold increase of ERK2 kinase activity was observed within 30 min when MCF-7 cells were treated with 0.1 microM vinorelbine. In contrast, the same treatment with paclitaxel resulted in a significant decrease of ERK2 kinase activity. We also demonstrated that elevated bcl-2 phosphorylation induced by vinorelbine is paralleled by decrease of a complex formation between bcl-2 and bax, cleavage of poly (ADP) ribose polymerase (PARP) protein, activation of caspase-7, and apoptosis. The levels of bcl-2 phosphorylation, bax, and PARP were not significantly affected by 2'-amino-3'-methoxyflavone (PD 98059), an ERK kinase specific inhibitor. Thus, our data suggest that the apoptosis induced by vinorelbine in MCF-7 cells is mediated through the bcl-2 phosphorylation/bax/caspases pathways, and that activation of ERK2 by vinorelbine does not directly lead to the drug-mediated apoptosis. Since decrease of PARP occurred quickly following the treatment of MCF-7 cells with either 0.1 microM of vinorelbine or paclitaxel, this protein may serve as an early indicator of apoptosis induced not only by DNA damaging agents, but also by antimicrotubule drugs.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Overexpressed androgen receptor linked to p21WAF1 silencing may be responsible for androgen independence and resistance to apoptosis of a prostate cancer cell line.

An androgen-independent (AI) prostate cancer cell line, derived recently from an LNCaP cell line maintained in androgen-poor conditions, has properties resembling a subgroup of advanced prostate cancers in that it has an overexpressed androgen receptor (AR), undetectable levels of p21WAF1 and prostate-specific antigen, and is resistant to apoptosis. The loss of prostate-specific antigen expression but not the p21WAF1 is attributable to gene silencing by hypermethylation. The high AR and undetectable p21WAF1 of AI cells, and lower AR but highly expressed p21WAF1 of androgen-dependent parental LNCaP cells, suggest a possibility of a functional link between these two proteins. Therefore, we examined the impact the modulation of AR will have on the expression of p21WAF1. Treatment of androgen-dependent cells with an androgen agonist, R1881, increased the AR protein level, whereas it simultaneously reduced the endogenous p21WAF1-protein 8-fold and the activity of a transiently transfected p21-promoter-reporter 10-fold. The down-regulation of p21WAF1 promoter appeared to be ARE mediated, dependent on AR, and not cell-type specific. Furthermore, a reduction of the AR level in AI cells by AR-antisense oligonucleotide increased the p21WAF1 promoter-reporter activity by approximately 4-fold, confirming a functional link between these two proteins. A strong, direct induction of p21WAF1 expression achieved by treatment of AI cells with trichostatin A produced a partial reversion of the AI phenotype evidenced by increased sensitivity of these cells to paclitaxel-induced apoptosis. Moreover, a reduction of AR level by antisense treatment, which also increased p21WAF1 expression, partially restored the androgen dependence of AI cells for growth. The functional link between AR dosage and p21WAF1 expression suggests that therapeutic reduction of AR protein in advanced prostate cancers with elevated AR levels may re-establish their hormone dependence and improve therapeutic response to repeated hormonal ablation and/or induction of apoptosis.

Apoptosis↗

PubMed2001

Human movement characteristics of target acquisition.

Objective. This paper deals with the problem of human movement characteristics of target acquisition. Method. A hypothetical model was posed by using experimental data. Result. The conception of final target size was put forward, an equation for calculating the movement time of target acquisition was obtained, and a new definition of index of difficulty was given. Conclusion. Analysis of experimental data showed that this equation could give a better description of target acquisition in a wide range.

Acceleration↗

PubMed2000

Synergism of cytotoxic effects of vinorelbine and paclitaxel in vitro.

Empiric combinations of vinca alkaloids with taxanes have been recently used in clinical oncology. To enhance the activity of these two classes of agents, we evaluated the sequence and duration of exposure, looking for synergistic effects. Cell lines DU 145, PC 3, LnCaP, LL 86, MCF7wt, and MCF7/ADR (NCI/ADR-RES) were incubated with varying concentrations of paclitaxel or vinorelbine. Cytotoxicity was evaluated by a semiautomated MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) method. Synergism or antagonism of these two agents either sequentially or in combination was determined by median effect analysis. Prolonged exposure of cells to either drug enhanced cytotoxic effect. Synergism or antagonism with vinorelbine and paclitaxel were both sequence dependent and cell line specific. In the case of MCF7wt, synergism was seen when a 48-hr exposure to vinorelbine preceded paclitaxel, whereas antagonism was noted when both agents were applied simultaneously or when the sequence was reversed. Concurrent vinorelbine and paclitaxel were synergistic in four of six cell lines when the exposure was extended to 96 hr but not for shorter durations of exposure. Sequential exposure of vinorelbine preceding paclitaxel or prolonged exposure to both agents concurrently needs to be tested clinically to determine whether the antitumor activity of this combination can be enhanced. In addition, these studies suggest concurrent administration of these two agents may lead to a less than optimal cytotoxic result.

Antineoplastic Agents, Phytogenic↗

PubMed2000

[Material selection and structural design of simulated space module for field].

OBJECTIVE: To select the suitable material for the structure of simulated space cabin to meet the special requirements which the unitary metallic material cannot do. METHOD: The structural material was selected through comparison between the mechanical properties of fiber reinforced plastics (FRP) and a few conventional metallic materials. The content and arrangement of the fibers in the composite material were suitably designed according to load condition and structural shape of the cabin. RESULT: High strength and high stiffness, light weight, anti-fatigue and shock proof were achieved for the whole module structure. It meets the medical and hygienic standard for hazardous gases. CONCLUSION: The structural design of fiber glass reinforced plastics composite module was proved to be successful. It reduced the weight of the module body, and increased the strength and toughness of the whole module.

Compressive Strength↗

PubMed2000

[Physical parameter measurement and quality assurance of X-knife].

The treatment of X-knife with linear accelerator, the results and the methods used in physical parameter measurement, are introduced in this paper. We also discusses some problems about quality control. It is proved that our results can be used in X-knife treatment.

Particle Accelerators↗

PubMed1999

Synergistic effect of estramustine and [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) on the inhibition of androgen receptor phosphorylation in LNCaP cells.

Estramustine phosphate has been used frequently alone or in combination with other drugs for the treatment of hormone-refractory prostate cancer. Estramustine is one of the major active metabolites of estramustine phosphate in vivo. We recently demonstrated that estramustine acts as an androgen antagonist, and the combination of estramustine with [3'-keto-Bmtl]-[Val2]-cyclosporine (PSC 833) results in synergistic cytotoxicity. Unlike other regulators of microtubules, such as paclitaxel, the present study demonstrated that estramustine alone or in combination with PSC 833 did not induce bcl-2 phosphorylation in LNCaP cells. No synergism between estramustine and PSC 833 in the induction of bcl-2 phosphorylation was obtained in MCF-7 cells exposed for 16 hr to estramustine (5-15 microM) and PSC 833 (5 microM). A significant synergistic antiandrogenic effect as measured by the inhibition of dihydrotestosterone-induced reporter gene luciferase expression in both wild-type and mutated androgen receptor (AR) cDNA-transfected HeLa cells was observed when the cells were exposed to estramustine and PSC 833. Treatment of LNCaP cells with estramustine alone (5-15 microM) resulted in a decrease of AR expression and phosphorylation. This effect was enhanced markedly by PSC 833. A strong correlation between AR phosphorylation and expression of the AR target gene PSA was obtained in dihydrotestosterone-stimulated LNCaP cells. The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808). Thus, our studies suggest that the synergism between estramustine and PSC 833 in LNCaP cells is a consequence of inhibition of AR expression and phosphorylation, thus leading to interruption of AR-mediated gene expression.

Antineoplastic Agents, Hormonal↗

PubMed1999

Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity.

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer.

Androgen Antagonists↗

PubMed1999

The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.

PURPOSE: Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways. CONCLUSION: Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.

Animals↗

PubMed1999

Anti-tumor effect of angiogenesis inhibitor TNP-470 on the human nasopharyngeal carcinoma cell line NPC/HK1.

The efficacy and targeting cells of angiogenesis inhibitor TNP-470 on human squamous cell nasopharyngeal carcinoma (NPC) were investigated. The colorimetric MTT assay was used to evaluate the IC50 values of NPC/HK1 cells and human dermal microvascular endothelial cells (HDMEC) for TNP-470. An NPC human tumor model was built by tumor-bearing nude mice using the NPC cell line of NPC/HK1. TNP-470 (30 mg/kg s.c.) was injected every other day. The results showed that the IC50 of NPC/HK1 cells for TNP-470 was 3.8 times higher than that of HDMEC. A significant difference in tumor volume between control and treatment groups was found after 7 days of treatment and increased thereafter. At the end of the treatment, tumor volume was 773.7 +/- 287.1 mm3 (n = 8) in the control group versus 454.5 +/- 132.8 mm3 (n = 8) in the treatment group (p = 0. 013); the ratio of the mean tumor volume in treated animals to that of control animals was 0.587, resulting a 41.3% decrease in tumor growth. The necrotic area was larger in the treatment group. Physical toxicity did not result from the treatment. These studies suggest that angiogenesis inhibitor TNP-470 is effective in the treatment of squamous cell NPC without obvious toxicity.

Antibiotics, Antineoplastic↗

PubMed1998

Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor.

Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer.

Androgen Antagonists↗

PubMed1997

Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells.

As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer. In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element. Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe. Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited. As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride. Our data indicate that inhibition of complex formation between SRBC and nuclear proteins due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells.

Consensus Sequence↗