• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.5001-5007
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• 2014

The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol ($E_2$) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-${\kappa}B$/p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bcl-xl. We found that on treatment with garcinol in MCF-7 cells, $E_2$-induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-${\kappa}B$/ac-p65 proteins in $E_2$-treated MCF-7 cells was increased, this being inhibited by garcinol but not ac-H4.The nuclear translocation of NF-${\kappa}B$/p65 in $E_2$-treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of $E_2$ on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-${\kappa}B$/p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by $E_2$. Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-${\kappa}B$ pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3945-3951
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• 2016

Background: Whether concurrent chemotherapy treatment is superior to radiotherapy alone as an adjuvant regimen for postoperative cervical carcinoma with risk factors remains controversial. Materials and Methods: A literature search strategy examined Pubmed, Embase, the Cochrane Library, the China National Knowledge Internet Web, the Chinese Biomedical Database and the Wanfang Database. Article reference lists and scientific meeting abstracts were also screened. Controlled trials comparing concurrent chemoradiotherapy versus radiotherapy alone in postoperative cervical cancer were included. The methodological quality of non-randomized controlled trials was evaluated using the Newcastle-Ottawa Scale. Randomized controlled studies were evaluated with the Cochrane handbook. A meta-analysis was performed with RevMan 5.3. Results: A total of 1,073 patients from 11 clinical trials were analysed, with 582 patients in the concurrent chemoradiotherapy group and 491 patients in the radiotherapy group. Hazard ratios (HR) of 0.47 (95% CI 0.31-0.72) and 0.50 (95% CI 0.35-0.72) were observed for overall survival and progression-free survival, indicating a benefit from the additional use of concurrent chemotherapy. Subgroup analyses demonstrated that cervical cancer with high risk factors significantly benefitted from concurrent chemotherapy when examining overall survival (HR 0.44, 95% CI 0.28-0.67) and progression-free survival (HR 0.48, 95% CI 0.33-0.70), but patients with intermediate risk factors showed no benefit from concurrent chemotherapy in overall survival (HR 1.72, 95% CI 0.28-10.41) and progression-free survival (HR 1.09, 95% CI 0.19-6.14). No significant differences were observed for grade 3-4 anaemia (risk ratio (RR) 3.87, 95% CI 0.69-21.84), grade 3-4 thrombocytopenia (RR 3.04, 95% CI 0.88-10.58), grade 3-4 vomiting or nausea (RR 1.71, 95% CI 0.27-10.96), or grade 3-4 diarrhoea (RR 1.40, 95% CI 0.69-2.83). Significant differences were observed for grade 3-4 neutropenia in favour of the radiotherapy group (RR 7.23, 95% CI 3.94-13.26). Conclusions: In conclusion, concurrent chemoradiotherapy improves survival in postoperative cervical cancer with high risk factors but not in those with intermediate risk factors.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.985-989
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• 2015

Background: Docetaxel, cisplatin, 5-fluorouracil (DCF) given every three weeks is an effective, but palliative regimen and significantly toxic especially in patients who have a low performance score. Here, we aimed to evaluate the efficacy and tolerability of a weekly formulation of DCF in locally advanced and metastatic gastric cancer patients. Materials and Methods: 64 gastric cancer patients (13 locally advanced and 51 metastatic) whose ECOG (Eastern Cooperative Oncology Group) performance status (PS) was 1-2 and who were treated with at least two cycles of weekly DCF protocol as first-line treatment were included retrospectively. The weekly DCF protocol included $25mg/m^2$ docetaxel, $25mg/m^2$ cisplatin, and 24 hours infusion of $750mg/m^2$ 5-fluorouracil, repeated every week. Disease and patient characteristics, prognostic factors, treatment response, grade 3-4 toxicity related to treatment, progression free survival (PFS) and overall survival (OS) were evaluated. Results: Of the patients, 41 were male and 23 were female; the median age was 63 (29-82) years. Forty-one patients were ECOG-1 and 23 were ECOG-2. Of the total, 81.2% received at least three cycles of chemotherapy. Partial response was observed in 28.1% and stabilization in 29.7%. Overall, the disease was controlled in 57.8% whereas progression was noted in 42.2%. The median time to progression was 4 months (95%CI, 2.8-5.2 months) and median overall survival was 12 months (95%CI, 9.2-14.8 months). The evaluation of patients for grade 3-4 toxicity revealed that 10.9% had anemia, 7.8% had thrombocytopenia and 10.9% had neutropenia. Non-hematologic toxicity included renal toxicity (7.8%) and thrombosis (1.6%). Conclusions: In patients with locally advanced or metastatic gastric cancer who were not candidates for DCF administered every-3-weeks, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10697-10703
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• 2015

The laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors occurring in the head and neck. Tumor necrosis factor related apoptosis induce ligand (TRAIL) and TRAIL-receptors (DR4, DR5, DcR1, DcR2) are known as important members of TRAIL-mediated biochemical signaling pathway. Associations between polymorphisms in these genes and clinicopathological characteristics of human laryngeal carcinoma are not well defined. This study therefore aimed to investigate a possible relationship among the TRAIL and TRAIL-DR4 polymorphisms and sTRAIL levels in the risk or progression of LSCC. A total of 99 patients with laryngeal cancer and 120 healthy subjects were enrolled in the study. DR4 C626G and TRAIL 1595 C/T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sTRAIL levels were measured by ELISA. There were significant differences in the distribution of DR4 C626G genotypes and frequencies of the alleles between laryngeal cancer patients and controls (p<0.001) but not in TRAIL 1595 C/T. We found the increased frequency of the DR4 C626G homozygote CC genotype in patients than in controls (p<0.001). Haplotype analysis revealed that there was also a statistically significant relationship between TRAIL and TRAIL-DR4 polymorphisms and laryngeal cancer. Serum sTRAIL levels in the laryngeal patients with CC genotype who had advanced tumour stage were lower than those of patients with early tumor stage (p=0.014). Our findings suggest that DR4 C626G genotypes and sTRAIL levels might be associated with progression of laryngeal cancer in the Turkish population.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2561-2567
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• 2015

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death worldwide. Our study aimed to reveal molecular mechanisms. Microarray data of GSE15471 (including 39 matching pairs of pancreatic tumor tissues and patient-matched normal tissues) was downloaded from Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in PDAC tissues compared with normal tissues by limma package in R language. Then GO and KEGG pathway enrichment analyses were conducted with online DAVID. In addition, principal component analysis was performed and a protein-protein interaction network was constructed to study relationships between the DEGs through database STRING. A total of 532 DEGs were identified in the 38 PDAC tissues compared with 33 normal tissues. The results of principal component analysis of the top 20 DEGs could differentiate the PDAC tissues from normal tissues directly. In the PPI network, 8 of the 20 DEGs were all key genes of the collagen family. Additionally, FN1 (fibronectin 1) was also a hub node in the network. The genes of the collagen family as well as FN1 were significantly enriched in complement and coagulation cascades, ECM-receptor interaction and focal adhesion pathways. Our results suggest that genes of collagen family and FN1 may play an important role in PDAC progression. Meanwhile, these DEGs and enriched pathways, such as complement and coagulation cascades, ECM-receptor interaction and focal adhesion may be important molecular mechanisms involved in the development and progression of PDAC.

• Biomolecules & Therapeutics
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• v.20 no.2
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• pp.177-182
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• 2012

Tetrazolium violet is a tetrazolium salt and has been proposed as an antitumor agent. In this study, we reported for the first time that tetrazolium violet not only inhibited human lung cancer A549 cell proliferation but also induced apoptosis and blocked cell cycle progression in the G1 phase. The results showed that tetrazolium violet significantly decreased the viability of A549 cells at $5-15{\mu}M$. Tetrazolium violet -induced apoptosis in A549 cells was confirmed by H33258 staining assay. In A549, tetrazolium violet blocked the progression of the cell cycle at G1 phase by inducing p53 expression and further up-regulating p21/WAF1 expression. In addition, an enhancement in Fas/APO-1 and its two forms of ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), as well as caspase, were responsible for the apoptotic effect induced by tetrazolium violet. The conclusion of this study is that tetrazolium violet induced p53 expression which caused cell cycle arrest and apoptosis. These findings suggest that tetrazolium violet has strong potential for development as an agent for treatment lung cancer.

• Journal of Marine Bioscience and Biotechnology
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• v.12 no.2
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• pp.91-98
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• 2020

Stichopus japonicas (red sea cucumbers) inhabit the coastal sea surrounding Jeju Island, South Korea, and are thought to have various medicinal properties. In this study, we investigated the anticancer activity of a red sea cucumber (S. japonicus) collected from Jeju Island. We obtained the red sea cucumber extract (RSCE), and observed that it inhibited the tumor cell growth and increased reactive oxygen species (ROS) production associated with the induction of apoptosis through the mitogen-activated protein kinase (MAPK) pathway in murine colon carcinoma cells (CT-26). Treatment with RSCE and N-acetylcysteine, which is a ROS scavenger, increased ROS production and apoptosis via the regulation by the MAPK pathway on the ERK and JNK compared with the nontreated group. Therefore, RSCE promotes ROS-mediated suppression of the ERK and JNK activation, and subsequently inhibits cancer progression, suggesting that RSCE may be beneficial in treating colon carcinoma.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.281-290
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• 2024

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.4
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• pp.745-755
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• 2002

To examine the effects of Yunpyesan on the cell proliferation of A549 human lung carcinoma cell line, we performed various experiments such as dose-dependent effect of Yunpyesan on cell proliferation and viability, morphological changes, quantification of apoptotic cell death and alterations of apoptosis/cell cycle-regulatory gene products. Yunpyesan declined cell viability and proliferation in both a dose- and a time-dependent manner. The anti-proliferative effect by Yunpyesan treatment in A459 cells was associated with morphological changes such as membrane shrinking and cell rounding up. Yunpyesan Induced apoptotic cell death in a time-dependent manner, which was associated with degradation of poly-(ADP-ribose) polymerase (PARP), an apoptotic target protein, without alterations of the balance between Bcl-2 and Bax expressions. DNA flow cytometric histograms showed that population of G1 phase of the cell cycle was increased by Yunpyesan treatment in a dose-dependent manner. Western blot analysis revealed that cyclin D1 and A were reduced by Yunpyesan treatment, whereas cyclin dependent kinase (Cdk) inhibitor p27 was markedly increased in a time-dependent fashion. The level of tumor suppressor p53 proteins was also increased by Yunpyesan treatment and its increase might be linked to increase of Cdk inhibitor p27. In addition, Mdm2, negative regulator of p53, was down-regulated by Yunpyesan treatment. Since the expression of retinoblastome protein (pRB), a key regulator of G1/S progression, was reduced by Yunpyesan treatment, we supposed that phosphorylation of pRB might be also blocked. The present results indicated that Yunpyesan-induced inhibition of lung cancer cell proliferation is associated with the induction of apoptosis and the blockage of G1/S progression.

• BMB Reports
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• v.39 no.6
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• pp.649-655
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• 2006

The NSAID activated gene (NAG-1), a member of the TGF-$\beta$ superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-$\beta$ superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-$3{\beta}$ pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.