• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3781-3789
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• 2012

Background: Pancreatic cancer is one of the most aggressive tumors with a dismal prognosis. The membrane cytoskeletal crosslinker Ezrin participates in several functions including cell proliferation, adhesion, motility and survival. There is increasing evidence that Ezrin is overexpressed in vast majority of malignant tumors and regulates tumor progression. However, its roles in pancreatic cancer remain elusive. Methods: Three pairs of specific Ezrin siRNAs were designed and synthetized and screened to determine the most efficient one for construction of a hairpin RNA plasmid targeting Ezrin. After transfection into the Panc-1 pancreatic cancer cell line, real-time quantitative PCR and Western blotting were performed to examine the expression of mRNA and protein. The MTT method was applied to examine the proliferation and the drug sensibility to Gemcitabine. Flow cytometry was used to assess the cycle and apoptosis, while capacity for invasion was determined with transwell chambers. Furthermore, we detected phosphorylated-Erk1/2 protein and phosphorylated-Akt protein by Western blotting. Results: Real-time quantitative PCR and Western blotting revealed that Ezrin expression was notably down-regulated at both mRNA and protein levels by RNA interference (P< 0.01). Proliferation was inhibited and drug resistance to gemcitabine was improved (P< 0.05). Flow cytometry showed that the proportion of cells in the G1/G0 phase increased (P< 0.01), and in G2/M and S phases decreased (P< 0.05), with no apparent differences in apoptosis (P> 0.05). The capacity for invasion was markedly reduced (P< 0.01). In addition, down-regulating Ezrin expression had no effect on phosphorylated-Akt protein (P>0.05), but could decrease the level of phosphorylated-Erk1/2 protein (P< 0.05). Conclusions: RNA interference of Ezrin could inhibit its expression in the pancreatic cancer cells line Panc-1, leading to a potent suppression of malignant behavior in vitro. Assessment of potential as a target for pancreatic cancer treatment is clearly warranted.

• Journal of Pharmaceutical Investigation
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• v.34 no.6
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• pp.459-463
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• 2004

CR 2945, a $gastrin/CCK_B$ receptor antagonist, was conjugated to liposome and tested for the targeting of pancreatic cancer cells in vitro. Successful conjugation was confirmed by FTIR and NMR. The size of CR 2945-conjugated liposome was about 500 nm in diameter, with the zeta-potential being -16.5 mV. In vitro anti-cancer activity of this formulation with or without gemcitabine encapsulated was tested on human pancreatic cancer cells, PANC-1. The growth inhibitory effect of gemcitabine-encapsulating CR 2945-conjugated liposome was found to be 10-fold more potent than that of gemcitabine-encapsulating non-conjugated liposome, suggesting that CR 2945 could be used as a potential cancer targeting moiety by conjugating into liposome.

• Journal of Applied Biological Chemistry
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• v.65 no.2
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• pp.83-88
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• 2022

Although it has been intensively studied over the past few decades, pancreatic cancer remains one of the most lethal cancers. Eriodictyol, a plant-derived flavonoid mainly found in citrus fruits, exerts diverse biological effects, including anti-oxidant, anti-cancer, and anti-inflammatory properties. In this study, we investigated the anticancer properties of eriodictyol and its mechanisms of action in pancreatic cancer cells. In both SNU213 and Panc-1 cells, eriodictyol decreased viability, induced apoptosis, and decreased clonogenicity. In addition, eriodictyol treatment increased the phosphorylation level of JNK and decreased the phosphorylation levels of ERK, FAK, and AKT. These observations provide insight into the molecular mechanisms of eriodictyol-induced apoptosis in pancreatic cancer cell lines, and could contribute to the development of candidate compounds for treating pancreatic cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7529-7536
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• 2013

Background and Aims: MicroRNA-21 (miR-21) is reported to be overexpressed and to contribute to proliferation, apoptosis and gemcitabine resistance in pancreatic ductal adenocarcinomas (PDACs). The aims of this study were to explore regulation of miR-21 expression by epigenetic change and its impact on chemoresistance and malignant properties of of pancreatic cancer. Materials and methods: We retrospectively collected 41 cases of advanced pancreatic cancer patients who were sensitive or resistant to gemcitabine and assessed levels of serum circulating miR-21 for correlation with cytotoxic activity. Histone acetylation in the miR-21 promoter was also studied in gemcitabine-sensitive and gemcitabine-resistant PDAC cells. Gemcitabine-resistant HPAC and PANC-1 cells were transfected with pre-miR-21 precursors (pre-miR-21) and antisense oligonucleotides (anti-miR-21), and were treated with TSA. Finally, invasion and metastasis assays were performed and alteration in mir-21, PTEN, AKT and pAKT level was evaluated in these cells. Results: Serum miR-21 levels were increased in gemcitabine-resistant PDAC patients compared with gemcitabine-sensitive subjects. The miR-21 levels were increased in 6 PDAC cells treated with gemcitabine significantly, associated with 50% inhibitory concentrations ($IC_{50}s$). Histone acetylation levels at miR-21 promoter were increased in PDAC cells after treatment with gemcitabine. Enhanced invasion and metastasis, increased miR-21 expression, decreased PTEN, elevated pAKT level were demonstrated in gemcitabine-resistant HPAC and PANC-1 cells. Pre-miR-21 transfection or TSA treatment further increased invasion and metastasis ability, decreased PTEN, and elevated pAKT levels in these two lines. In contrast, anti-miR-21 transfection could reverse invasion and metastasis, and PTEN and pAKT expressions induced by gemcitabine. Conclusions: MiR-21 upregulation induced by histone acetylation in the promoter zone is associated with chemoresistance to gemcitabine and enhanced malignant potential in pancreatic cancer cells.

• Journal of Applied Biological Chemistry
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• v.63 no.4
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• pp.457-462
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• 2020

Pancreatic cancer is among the most difficult-to-treat tumors. More than half of patients with this cancer have very few symptoms at the early stages, allowing the development of distant metastases and resistance to cancer treatment. In this study, we found that Juniperus chinensis extract (JCX) decreased the cell viability and migration activity of PANC-1 and SNU-213 pancreatic cancer cells in a dose-dependent manner. JCX increased caspase-3 activation and generation of reactive oxygen species (ROS). N-acetylcysteine treatment blocked JCX-induced ROS generation and the negative effects on pancreatic cancer cell viability. In addition, JCX down-regulated the levels of phospho-focal adhesion kinase (p-FAK) and phospho-extracellular signal-regulated kinase (p-ERK). Together, these results indicate that JCX induces apoptosis in human pancreatic cancer cell lines through ROS production, downregulating FAK/ERK signaling and activating caspase-3. We propose that JCX-derived compounds represent candidates for the development of alternative medicines for the treatment of pancreatic cancer.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.609-617
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• 2017

Pancreatic cancer is one of the most lethal and aggressive cancers in the world. However, no effective treatment is currently available for pancreatic cancer. The objective of this study was to determine the anti-pancreatic cancer effect of ${\alpha}$-mangostin (${\alpha}M$) and ${\gamma}$-mangostin (${\gamma}M$) extracted from the pericarp of Garcinia mangostana L.. Both ${\alpha}$M and ${\gamma}M$ reduced the viability of pancreatic cancer cells MIA PaCa-2 and PANC-1 in a dose-dependent manner. These compounds induced apoptosis by increasing c-PARP and c-Caspase 3 levels. They also induced autophagy by increasing levels of microtubule-associated protein 1A/1B light chain 3B (LC3II) in both cell lines while decreasing sequestosome 1 (p62) in MIA PaCa-2. Both ${\alpha}$M and ${\gamma}M$ induced autophagy through increasing phosphorylation levels of AMP-activated protein kinase (p-AMPK) and p38-mitogen activated protein kinase (p-p38) while decreasing phosphorylation level of mammalian target of rapamycin complex 1 (p-mTOR). Of various microRNAs (miRNA), miR-18a was found to be a putative regulatory miRNA for autophagy induced by ${\alpha}$M or ${\gamma}M$. In combination with gemcitabine, a compound frequently used in pancreatic cancer treatment, ${\alpha}$M and ${\gamma}M$ showed synergistic anti-cancer effects in MIA PaCa-2. Collectively, these results suggest that ${\alpha}$M and ${\gamma}M$ can induce apoptosis and autophagy in pancreatic cancer cells and that their anti-cancer effect is likely to be associated with miR-18a. In conclusion, ${\alpha}$M and ${\gamma}M$ might be used as a potential new therapy for pancreatic cancer.

• The Journal of Internal Korean Medicine
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• v.40 no.1
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• pp.70-88
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• 2019

Objective: This study investigated the trends in pancreatic cancer research on Korean medicine in order to establish a direction for further study. Methods: Pancreatic cancer research on Korean medicine was reviewed using databases such as OASIS, KoreanTK, KISS, RISS, KISTI, and NDSL. The search terms were "pancreatic cancer" "Korean medicine," and "herbal medicine." There was no restriction on publication dates, and the reviewed studies were analyzed according to the type of research. Results: Nineteen studies were reviewed. The numbers and types of research were as follows: 9 clinical studies including case reports, 2 review studies, and 8 in vitro studies; there was no in vivo study. Among the clinical research were 3 descriptive studies and 6 case reports. The baseline characteristics and quality of life of pancreatic cancer patients were analyzed in the descriptive studies. In the case reports, interventions such as herbal medicine, pharmacopuncture, and acupuncture were used. Research articles on the review of pancreatic cancer were titled "Preliminary Study for Development of Korean Medicine Clinical Practice Guideline for Pancreatic Cancer" and "Systemic Review on the Tumor Dormancy Therapy." Cell lines such as PANC-1, MIA PaCa-2, and AsPC-1 were used for in vitro studies. These studies have reported decreased cell viability, induced apoptosis, and changes in cancer-related gene expression. Conclusion: Through this review, we found that using Korean medicine for treating pancreatic cancer is applicable. However, due to overall limited the number of study, the benefit of Korean medicine for pancreatic cancer may be substantiated to a limited degree. Better methodological quality and large controlled trials are expected to further quantify the therapeutic effect of Korean medicine.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4519-4525
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• 2014

Oleanolic acid (OA) is a nutritional component widely distributed in various vegetables. Although it has been well recognized for decades that OA exerts certain anti-tumor activity by inducing mitochondria-dependent apoptosis, it is still unclear that what molecular signaling is responsible for this effect. In this study, we employed cancer cell lines, A549, BXPC-3, PANC-1 and U2OS to elucidate the molecular mechanisms underlying OA anti-tumor activity. We found that activation of MAPK pathways, including p-38 MAPK, JNK and ERK, was triggered by OA in both a dose and time-dependent fashion in all the tested cancer cells. Activation was accompanied by cleavage of caspases and PARP as well as cytochrome C release. SB203580 (p38 MAPK inhibitor), but not SP600125 (JNK inhibitor) and U0126 (ERK inhibitor), rescued the pro-apoptotic effect of OA on A549 and BXPC-3 cells. OA induced p38 MAPK activation promoted mitochondrial translocation of Bax and Bim, and inhibited Bcl-2 function by enhancing their phosphorylation. OA can induce reactive oxygen species (ROS)-dependent ASK1 activation, and this event was indispensable for p38 MAPK-dependent apoptosis in cancer cells. In vivo, p38 MAPK knockdown A549 tumors proved resistant to the growth-inhibitory effect of OA. Collectively, we elucidated that activation of ROS/ASK1/p38 MAPK pathways is responsible for the apoptosis stimulated by OA in cancer cells. Our finding can contribute to a better understanding of molecular mechanisms underlying the antitumor activity of nutritional components.

• Korean Journal of Food Science and Technology
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• v.50 no.2
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• pp.209-215
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• 2018

To evaluate the radical scavenging activity of phenolic-rich fractions of Gardenia jasminoides, we first measured the levels of total polyphenols in hexane, ethyl acetate, and butanol fractions from the extract of G. jasminoides. The ethyl acetate fraction of G. jasminoides extract (GJ-EA) showed high level of phenolics, potent reducing power, and 2,2-diphenyl-1-picrylhydrazyl/2,2'-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid radical scavenging effect. In addition, GJ-EA inhibited the overproduction of nitric oxide in lipopolysaccharide-activated BV-2 microglia. Furthermore, we found that GJ-EA suppressed $H_2O_2$-induced PANC-1 pancreatic cancer cell proliferation in a concentration-dependent manner and also reduced their migratory ability. These results suggest that GJ-EA may be a good source for functional foods with antioxidant and chemo-preventive activities.

• Journal of Life Science
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• v.26 no.11
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• pp.1320-1329
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• 2016

The present study examined the cytotoxic effects of 1, 2, 3, 4, 6-penta-O-galloyl-${\beta}$-D-glucose (PGG), known as the pentahydroxy gallic acid ester of glucose, in the various human cancer cell lines (A-549, MDA-MB-231, U87-MG, MCF-7 and PANC-1), normal MRC-5 fetal fibroblasts, and dental papilla tissue- derived mesenchymal stem cells (DPSCs). Significantly (p<0.05) lower half maximal inhibitory concentration ($IC_{50}$) values were observed in the A-549 and MDA-MB-231 cells showing a high proliferation capacity, compared with other cancer and normal cell lines with a relatively low proliferation capacity. The population doubling time (PDT) was significantly (p<0.05) higher in the $10{\mu}M$ PGG-treated cell lines than those of untreated control cell lines. The present study demonstrated that the $IC_{50}$ value increases proportionally to the extending PDT. A high cell number with senescence-associated ${\beta}-galactosidase$ activity was also observed in the $10{\mu}M$ PGG-treated cells compared with those of untreated control cells. Moreover, the level of telomerase activity was significantly (p<0.05) decreased with $10{\mu}M$ PGG treatment, especially in A-549 and MDA-MB-231 cells showing a high proliferation capacity. Based on these observations, PGG could serve as a potent agent for cancer chemotherapy, as its treatment was more effective in cells with a high proliferation capacity.