Jeng-Jong Hwang - Academia.edu (original) (raw)

Papers by Jeng-Jong Hwang

Pharmaceutics

β-sitosterol (SITO) has been reported with anticancer effects; however, with poor bioavailability... more β-sitosterol (SITO) has been reported with anticancer effects; however, with poor bioavailability. The current study aimed to investigate whether liposomal encapsulated β-sitosterol (LS) has a better inhibition effect on tumor metastasis than β-sitosterol in a CT26/luc lung metastasis mouse model and the possible underlying mechanism. LS was liposomal-encapsulated SITO and was delivered to mice by oral gavage. The cell viability was determined by the MTT assay, and invasiveness of the tumor cells and related protein expression were evaluated with the invasion assay and Western blotting. For therapeutic efficacy evaluation, male BALB/c mice were treated with PBS, SITO, and LS once a day for 7 days prior to intravenous injections of CT26/luc cells; treatments were continued twice a week post-cell inoculation throughout the entire experiment. Tumor growth inhibition was monitored by bioluminescent imaging (BLI). IL-12, IL-18, and IFN-γ in the intestinal epithelium were determined by EL...

Anticancer research, 2009

This study aimed to develop a novel tumor-specific promoter gene linking sodium iodide symporter ... more This study aimed to develop a novel tumor-specific promoter gene linking sodium iodide symporter (NIS) gene to specifically target hepatocellular carcinoma in a mouse tumor model. A tumor-specific chimeric promoter for alpha-fetoprotein gene (AFP) was combined with hepatitis B virus (HBV) enhancer II to investigate radioiodine uptake in vitro and in vivo in hepatoma (HepG2) and nonhepatoma (ARO) cell lines after transfer of hNIS gene. A lentiviral vector carrying the hNIS gene was employed in vitro and in vivo. Radionuclide imaging was acquired for 30 min at 60 min after administration of 1241 to monitor hNIS gene expression in vivo using microPET. The highest radioiodide uptake of ARO and HepG2 clones which stably expressed hNIS gene were 87- and 208-fold higher than that of parental cells, respectively. After infection of lentivirus, hNIS gene controlled by cytomegavirus (CMV) promoter was expressed in both ARO and HepG2 cells, and hNIS gene induction by EIIAPA promoter was higher...

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2002

137 Cs contamination in living or agricultural environments may contribute to significant human i... more 137 Cs contamination in living or agricultural environments may contribute to significant human internal exposure and cause adverse health effects. Contamination by 137 Cs and other radionuclides was detected in a river valley in northern Taiwan, in the 1990s. Given that the radioactivity appeared to be widely distributed in soil, rice and several other food plants in the areas surrounding several communities in the late 1990s [Y.B. Nabyvanents, T.F. Gesell, M.H. Jen, W.P. Chang, Distribution of 137 Cs in soil along Ta-han River Valley in Tau-Yuan County in Taiwan, J. Environ. Radioact. 54 (2001) 391], its possible impact on local occupants was further studied. Ten subjects in three families residing continuously in the highly contaminated valley and 10 non-exposed subjects matched for age, sex, and cigarette smoking habits from neighboring communities were evaluated for micronucleus frequencies and for degenerative nuclear changes in urinary exfoliated epithelial cells (EE cells). Micronucleus frequencies (‰) were significantly higher in the exposed subjects (4.79 ± 1.21‰) than in the reference subjects (2.73 ± 0.59‰; Wilcoxon 2-sample test, P value 0.0004). There were also higher frequencies of EE cells with karyolysis and condensed chromatin in the exposed subjects than in reference subjects. These results indicate that genotoxic and/or mutagenic effects on urinary epithelial cells occur in human subjects who have resided for a long time in a radioactively contaminated environment.

Mutagenesis, 1999

Acute radiation exposure of humans was observed to induce various forms of cytogenetic damage, in... more Acute radiation exposure of humans was observed to induce various forms of cytogenetic damage, including increased frequencies of micronuclei and chromosomal aberrations. However, the cytogenetic effects of chronic low dose radiation exposure in vivo needs further characterization. Sixteen subjects with chronic low dose rates of γ-radiation exposure from 60 Co-contaminated steel in radioactive buildings were compared with seven non-exposed reference subjects for micronucleus frequencies after they relocated. By in situ hybridization using a digoxigenin-labeled anti-α all human centromere probe, the exposed subjects were shown to have a significant increase in cytochalasin B-modulated micronucleus (CBMN) frequencies, as well as a significant increase in centromere-positive (C⍣) CBMN, centromere-negative (C-) CBMN, total C⍣signals, single C⍣ MN signals and multiple C⍣ signals/1000 binucleated cells (BN). However, decreases in the ratios C⍣MN/C-MN and C⍣MN/total CBMN (%) were also noted in the exposed subjects. By mixed effects analysis, considering individuals from the same families, the C-MN and single C⍣ MN/ 1000 BN were both positively and moderately associated with previous cumulative exposure. When the time period of relocation post-exposure (relocation time or RT) was considered, total C⍣MN and multiple C⍣MN/1000 BN were negatively and significantly associated with RT. Moreover, the C⍣MN, C-MN, C⍣MN/C-MN ratio and single C⍣MN/1000 BN were all negatively and moderately associated with RT, but not with exposure dose. This suggested that acentromeric and single or multiple centromeric CBMN cytogenetic damage seems to disappear differentially in human subjects post chronic low dose radiation exposure.

In vivo (Athens, Greece)

Invasion by hepatocellular carcinoma (HCC) has been reported to occur via the up-regulation of nu... more Invasion by hepatocellular carcinoma (HCC) has been reported to occur via the up-regulation of nuclear factor-kappaB (NF-κB). Sorafenib can improve the overall survival in patients with HCC, however, the association of its inhibitory mechanisms with the inactivation of NF-κB remains unclear. Here, Huh7 cell line transfected with NF-κB-luc2 vector was used to study the effects of sorafenib on NF-κB activity, on expressions of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF), which were induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). TPA increased the NF-κB activity and the expressions of MMP-9 and VEGF significantly, but its effects were suppressed by sorafenib in a dose-dependent manner. Similar results were found with PD98059, an inhibitor of extracellular signal-regulated kinase (ERK). Furthermore, transfection of Huh7 cell with an inhibitor of kappaB-α mutant vector, led to reduced TPA-induced MMP-9 and VEGF mRNA expressions. Sorafenib inhib...

Oncology Reports

Tetrandrine (TET), a traditional Chinese clinical agent, has been used for the treatment of many ... more Tetrandrine (TET), a traditional Chinese clinical agent, has been used for the treatment of many diseases, including cancers. The purpose of the present study was to investigate the combined effects of TET and ionizing radiation (IR) on murine CT26 colorectal adenocarcinoma cells in vitro and in vivo. A CT26 cell line transfected with dual HSV-1 thymidine kinase and firefly luciferase (luc) reporter genes was used. The half-maximal inhibitory concentration (IC 50) of TET in CT26/tk-luc cells was ~10 µM. An additive effect was observed after combination of both agents based on a colony formation assay. Apoptosis and cleaved caspase-3 levels were increased significantly in cells after combination treatment, as shown by flow cytometric analysis, DNA fragmentation and western blotting. However, tumor growth inhibition and therapeutic efficacy of TET combined with IR in vivo were identified to be synergistic, as monitored by tumor growth delay time, measured with a digital caliper. A significant inhibition of tumor growth was identified in the combination group compared with the radiation only group. Furthermore, non-invasive bioluminescent imaging (BLI) and gamma scintigraphy were also used to evaluate therapeutic efficacy. Both modalities revealed that the best tumor growth control was under combination treatment among all groups. The present study demonstrated that TET is not only beneficial for chemotherapy, but also has potential as a radiosensitizer for the treatment of cancer.

Requirements of large numbers of transferred T cells and various immunosuppressive factors and ce... more Requirements of large numbers of transferred T cells and various immunosuppressive factors and cells in the tumor microenvironment limit the applications of adoptive T cells therapy (ACT) in clinic. Accumulating evidences show that chemotherapeutic drugs could act as immune supportive instead of immunosuppressive agents when proper dosage is used, and combined with immunotherapy often results in better treatment outcomes than monotherapy. Controversial immunomodulation effects of sorafenib, a multi-kinases inhibitor, at high and low doses have been reported in several types of cancer. However, what is the range of the low-dose sorafenib will influence the host immunity and responses of ACT is still ambiguous. Here we used a well-established E.G7/OT-1 murine model to understand the effects of serial low doses of sorafenib on both tumor microenvironment and transferred CD8+ T cells and the underlying mechanisms. Sorafenib lowered the expressions of immunosuppressive factors, and enhan...

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Bioscience Reports

Androgen deprivation therapy (ADT) is one of the typical treatments used for patients with prosta... more Androgen deprivation therapy (ADT) is one of the typical treatments used for patients with prostate cancer (PCa). ADT, however, may fail when PCa develops castration-resistance. Fatty acid synthase (FASN), a critical enzyme involved in fatty acid synthesis, is found to be up-regulated in PCa. Since enzalutamide and ADT are frequently used for the treatment of PCa, the present study aimed to unravel the underlying mechanism of combination of orlistat, an FASN inhibitor, and enzalutamide using PC3 cell line; and orlistat and castration in PC3 tumor-bearing animal model. Cytotoxicity was determined by AlamarBlue assay. Drug effects on the cell cycle and protein expressions were assayed by the flow cytometry and Western blot. Electromobility shift assay was used to evaluate the NF-κB activity. The tumor growth delay, expressions of the signaling-related proteins, and histopathology post treatments of orlistat and castration were evaluated in PC3 tumor-bearing mouse model. The results sh...

Oncology Letters

Trichostatin A (TSA), a hydroxamate histone deacetylase inhibitor, is a compound that has been id... more Trichostatin A (TSA), a hydroxamate histone deacetylase inhibitor, is a compound that has been identified to induce anticancer activity. The aim of the present study was to investigate whether sorafenib, in combination with TSA, was able to augment the anticancer effects of TSA, identifying an optimum treatment time plan and the potential underlying molecular mechanisms involved in human hepatocellular carcinoma (HCC) in vitro. Huh7/nuclear factor-κB (NF-κB)-luc2 cells were treated with TSA or sorafenib alone, or sorafenib, prior to, in combination with or following TSA treatment. Huh7/NF-κB-luc2 cell viability following TSA treatment was determined using an MTT assay, and NF-κB activity was analyzed. In addition, the expression levels of NF-κB-regulated downstream effector proteins were assayed by western blotting. Inhibitors of mitogen-activated protein kinases (MAPKs), protein kinase B (AKT) and mutant inhibitor of NF-κBα (IκBαM) vectors were used to confirm the function of the NF-κB signal transduction pathways in response to the effects of sorafenib combined with TSA against HCC. The results of the present study indicated that pre-treatment with sorafenib followed by TSA inhibited the cell viability compared with other treatment modalities, and prevented TSA-induced extracellular-signal-regulated kinase (ERK)/NF-κB activity and expression of downstream effector proteins. It was further demonstrated that IκBαM vector sensitized Huh7/NF-κB-luc2 cells to TSA, thus it was possible to reverse TSA-induced NF-κB activity using PD98059, a MAPK/ERK kinase inhibitor. In conclusion, sorafenib pre-treatment may increase the efficacy of subsequent TSA treatment in HCC. Furthermore, sorafenib pre-treatment is hypothesized to sensitize HCC to TSA via the inhibition of the MEK/ERK/NF-κB signal transduction pathway.

Journal of virology

A retroviral vector for the enhanced expression of the herpes simplex virus thymidine kinase (HSV... more A retroviral vector for the enhanced expression of the herpes simplex virus thymidine kinase (HSV tk) gene was developed by using a tetracycline-responsive expression system (TRES). The two components of the TRES, the chimeric transactivator (tTA) and the corresponding tTA-binding cis element (tetO), were both incorporated into a retroviral vector and resulted in high levels of tk gene expression from tetO in target cells. Amphotropic virus supernatants from stable producer cells, generated by the retroviral vector containing the TRES, gave titers of 10(4) to 10(5) G418-resistant CFU/ml on murine NIH 3T3 cells. The retroviral vector (G1tTA-[tetOTkINa]R), in which tetO was used in the opposite orientation relative to viral transcription, was capable of transducing tk and neo genes into murine NIH 3T3 cells to yield a high level of tk gene expression. TK enzyme activity in NIH 3T3 cells transduced by this vector was 417-fold higher than in control cells. This increased TK activity was...

Scientific Reports

Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent... more Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Comb...

Inflammation Research

Objective and designTo investigate the amelioration effects of quetiapine on rheumatoid arthritis... more Objective and designTo investigate the amelioration effects of quetiapine on rheumatoid arthritis with RAW 264.7 macrophage and collagen-induced arthritis (CIA) DBA/1J mouse model.SubjectsRAW 264.7 macrophage and DBA/1J mice.Treatment Lipopolysaccharide and collagen.MethodsRAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) followed by quetiapine treatments were investigated. Activations of CD80 and CD86 were analyzed by flow cytometry. Pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β were analyzed by ELISA. Proteins involved in signaling pathways related to the formation of rheumatoid arthritis were assayed by Western blotting. Therapeutic efficacy of quetiapine in CIA mouse model was also assayed. 18F-FDG/micro-PET was used to monitor the inflammation status in the joints, and the severity of bone erosion was evaluated with micro-CT and H&E staining.ResultsThe inhibition of pro-inflammatory cytokines by quetiapine was found through the ERK and AKT phosphorylation and subsequent NF-κB and CREB signaling pathways. Pro-inflammatory cytokines such as IL-17, IL-6 and IL-1β were decreased, while immunosuppressive factors such as TGF-β and IL-10 were increased in CIA mice treated with quetiapine. Notably, no uptake of 18F-FDG and bone erosion was found with micro-PET images on days 32 and 43 in the quetiapine-treated and normal control groups. However, significant uptake of 18F-FDG could be observed in the CIA group during the same time course. Similar results were further verified with ex vivo autoradiography.ConclusionTaken together, these results suggest that quetiapine is a potential anti-inflammatory drug, and may be used as an adjuvant for the treatment of rheumatoid arthritis.

International Journal of Gerontology

Journal of Clinical Medicine

Esophageal cancer prognosis remains poor in current clinical practice. We previously reported tha... more Esophageal cancer prognosis remains poor in current clinical practice. We previously reported that moscatilin can induce apoptosis and mitotic catastrophe in esophageal cancer cells, accompanied by upregulation of polo-like kinase 1 (Plk1) expression. We aimed to validate in vitro activity and Plk1 expression in vivo following moscatilin treatment and to examine the treatment’s radiosensitizing effect. Human esophageal cancer cells were implanted in nude mice. Moscatilin was intraperitoneally (i.p.) injected into the mice. Tumor size, body weight, white blood cell counts, and liver and renal function were measured. Aberrant mitosis and Plk1 expression were assessed. Colony formation was used to measure survival fraction after radiation. Moscatilin significantly suppressed tumor growth in mice bearing human esophageal xenografts without affecting body weight, white blood cell counts, or liver and renal function. Moscatilin also induced aberrant mitosis and apoptosis. Plk1 expression ...

Asian Pacific Journal of Cancer Prevention

To assess the risk of cancer incidence after medical radiation exposure for coronary artery disea... more To assess the risk of cancer incidence after medical radiation exposure for coronary artery disease (CAD), a retrospective cohort study was conducted based on Taiwan's National Health Insurance Research Database (NHIRD). Patients with CAD were identified according to the International Classification of Diseases code, 9th Revision, Clinical Modification (ICD-9-CM), and their records of medical radiation procedures were collected from 1997 to 2010. A total of 18,697 subjects with radiation exposure from cardiac imaging or therapeutic procedures for CAD were enrolled, and 19,109 subjects receiving cardiac diagnostic procedures without radiation were adopted as the control group. The distributions of age and gender were similar between the two populations. Cancer risks were evaluated by age-adjusted incidence rate ratio (aIRR) and association with cumulative exposure were further evaluated with relative risks by Poisson regression analysis. A total of 954 and 885 subjects with various types of cancers in both cohorts after following up for over 10 years were found, with incidences of 409.8 and 388.0 per 100,000 person-years, respectively. The risk of breast cancer (aIRR=1.85, 95% confidence interval: 1.14-3.00) was significantly elevated in the exposed female subjects, but no significant cancer risk was found in the exposed males. In addition, cancer risks of the breast and lung were increased with the exposure level. The study suggests that radiation exposure from cardiac imaging or therapeutic procedures for CAD may be associated with the increased risk of breast and lung cancers in CAD patients.

International Journal of Oncology

The tumor suppressor p21 WAF/CIP1 mediates the proliferation arrest via p53-dependent or-independ... more The tumor suppressor p21 WAF/CIP1 mediates the proliferation arrest via p53-dependent or-independent gene transactivation following distinct environmental stresses. In this study, we show that direct destabilization of the actin cytoskeleton by actin-targeting reagents leads to a p53-independent up-regulation of p21 WAF/CIP1. The actintargeting agent cytochalasin B (10 μM) quickly disrupted the actin cytoskeleton of p53 wild-type and p53-null cells accompanied by up-regulation of p21 WAF/CIP1. Nevertheless, both total p53 and ser-15 phosphorylated p53 were not accumulated concomitantly, compared to the effect caused by ionizing irradiation. P53-independent up-regulation of p21 WAF/CIP1 was also observed by two other actin-targeting agents cytochalasin D and latrunculin B, but not by the microtubule inhibitor colcemid. Furthermore, we showed that p21 WAF/CIP1 mRNA level was not increased, whereas the protein degradation was delayed. A reduction of ubiquitination for p21 WAF/CIP1 protein was detected using immunoprecipitation/immunoblot analysis. Up-regulation of p21 WAF/CIP1 was not associated with cytotoxicity induced by cytochalasin B that influenced DNA integrity and plating efficiency only after 24 h of treatment. In addition, upregulated p21 WAF/CIP1 was accompanied by reduction of phosphorylation on retinoblastoma (Rb) protein in p53-null cells, implying that p21 WAF/CIP1 might in part account for the molecular regulation of cytochalasin B induced G1 phase arrest. Together, current results suggest that p21 WAF/CIP1 level can be mediated by actin organization in the absence of p53 via a post-transcriptional machinery, and it may contribute to the growth ablation by agents targeting the actin cytoskeleton.

Oncotarget, 2016

Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because cur... more Patients with unresectable hepatocellular carcinoma (HCC) usually have poor prognosis because current monotherapy including surgery, chemotherapy and radiotherapy (RT) are not effective. Combination therapy may be effective to overcome this clinical problem. Here, we proposed the combination of sorafenib and RT, which have been applied in HCC treatment, could improve the treatment outcome of HCC. Our previous study showed that sorafenib could suppress the expression of NF-κB which is related to the chemo-and radio-resistance. Nevertheless, the expression of NF-κB is oscillatory and is affected by the treatments. Thus, understanding the oscillation of NF-κB expression would be beneficial for determining the optimal treatment schedule in combination therapy. Here established Huh7/NF-κB-tk-luc2/ rfp cell line, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, EMSA, and NF-κB molecular imaging. These findings suggest that pretreatment of sorafenib with RT may be the ideal treatment schedule for the treatment of HCC.

Biomedicine & pharmacotherapy = Biomédecine & pharmacothérapie, 2016

Lupeol has been shown with anti-inflammation and antitumor capability, however, the poor bioavail... more Lupeol has been shown with anti-inflammation and antitumor capability, however, the poor bioavailability limiting its applications in living subjects. Lupeol acetate (LA), a derivative of lupeol, shows similar biological activities as lupeol but with better bioavailability. Here RAW 264.7 cells and bone marrow-derived macrophages (BMDMs) stimulated by lipopolysaccharide (LPS) were treated with 0-80μM of LA, and assayed for TNF-α, IL-1β, COX-2, MCP-1 using Western blotting. Moreover, osteoclatogenesis was examined with reverse transcription PCR (RT-PCR) and tartrate-resistant acid phosphatase (TRAP) staining. For in vivo study, collagen-induced arthritis (CIA)-bearing DBA/1J mice were randomly separated into three groups: vehicle, LA-treated (50mg/kg) and curcumin-treated (100mg/kg). Therapeutic efficacies were assayed by the clinical score, expression levels of serum cytokines including TNF-α and IL-1β, (18)F-fluorodeoxyglucose ((18)F-FDG) microPET/CT and histopathology. The results...