[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer remains one of the leading causes of cancer-related deaths, due to aggressive growth, high metastatic rates during the early stage and the lack of an effective therapeutic approach. We previously showed that Qingyihuaji (QYHJ), a seven-herb Chinese medicine formula, exhibited significant anti-cancer effects in pancreatic cancer, associated with modifications in the tumor microenvironment, particularly the inhibition of cancer-associated fibroblast (CAF) activation. In the present study, we generated CAF and paired normal fibroblast (NF) cultures from resected human pancreatic cancer tissues. We observed that CAFs exhibited an enhanced capacity for inducing pancreatic cancer cell migration and invasion compared with NFs, while QYHJ-treated CAFs exhibited decreased migration and invasion-promoting capacities in vitro. The results of further analyses indicated that compared with NFs, CAFs exhibit increased CXCL1, 2 and 8 expression, contributing to the enhanced invasion-promoting capacities of these cells, while QYHJ treatment significantly suppressed CAF proliferation activities and the production of CAF-derived CXCL1, 2 and 8. These in vitro observations were confirmed in mice models of human pancreatic cancer. Taken together, these results suggested that suppressing the tumor-promoting capacity of CAFs through Chinese herbal medicine attenuates pancreatic cancer cell invasion.
PLoS ONE 01/2014; 9(4):e96177. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early metastasis is a major biological feature of pancreatic cancer. The current study examined whether silencing Slc38a1, a gene involved in energy metabolism, using short hairpin RNA (shRNA) could inhibit the growth, migration, and invasiveness of pancreatic cancer cells.
A series of Slc38a1 shRNAs were designed and cloned into the pGPU6/GFP/Neo vectors. An shRNA with the most efficacious inhibitory action on SCL38A1 expression (65% inhibition) upon screening in DH5α bacteria was used to transfect SW1990 human pancreatic cancer cells. Cell growth, migration, and invasiveness were examined using cell counting kit-8, Boyden chamber without and with Matrigel, respectively.
Transfection of SW1990 cells with the SLCs38A1 shRNA significantly decreased the proliferation (P<0.0001) and migratory potential (by 46.7%, P=0.0399) of the cancer cells. Invasiveness, however, was not affected.
Inhibiting Slc38a1 using shRNA technology could decrease the growth and migration of representative pancreatic cancer cells. However, the fact that invasiveness was not affected suggested that SLC38A1 is unlikely to be responsible for early metastasis.
Chinese Journal of Cancer Research 10/2013; 25(5):514-519. · 0.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticaner potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitined proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.
Toxicology and Applied Pharmacology 09/2013; · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor resistance to radiation is a challenge to treatment of patients with pancreatic cancer. Improving our understanding of the mechanisms of radioresistance could lead to strategies to increase patients' response to therapy. We investigated the roles of microRNAs (miRNAs) involved in radioresistance of pancreatic cancer cells.
We established radioresistant pancreatic cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. We transfected pancreatic cancer cells with miRNA mimics or inhibitors and evaluated their effects on cell radiosensitivity using a clonogenic survival assay. The effects of miRNA on autophagy were determined by transmission electron microscopy and immunoblot analysis. We used a luciferase reporter assay to identify mRNA targets of specific miRNAs.
Radioresistant pancreatic cancer cells had reduced levels of the miRNA MIR23B and increased autophagy, compared with cells that were not radioresistant. Overexpression of MIR23B inhibited radiation-induced autophagy, whereas an inhibitor of MIR23B promoted autophagy in pancreatic cancer cells. Overexpression of MIR23B sensitized pancreatic cancer cells to radiation. The target of MIR23B, ATG12, was overexpressed in radioresistant cells; levels of ATG12 protein correlated with the occurrence of autophagy. Expression of MIR23B blocked radiation-induced autophagy and sensitized pancreatic cancer cells to radiation. We observed an inverse correlation between level of MIR23B and autophagy in human pancreatic cancer tissue samples.
In pancreatic cancer cells, reduced levels of the miRNA MIR23B increase levels of ATG12 and autophagy to promote radioresistance. MIR23B might be used to increase the sensitivity of pancreatic cancer cells to radiation therapy.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is an almost universally fatal disease resulting from early invasion of adjacent structures and metastasis and the lack of an effective treatment modality. Our previous studies have shown that Qingyihuaji Formula (QYHJ), a seven-herb Chinese medicine formula, had significant anti-cancer effects in pancreatic cancer. Here, we examined the effects of QYHJ on pancreatic cancer cell invasion and metastasis and the potential associated mechanism(s). We found that QYHJ inhibited both tumor growth and metastasis in nude mice with human pancreatic cancer cell xenografts. Further study indicated that QYHJ inhibited epithelial-to-mesenchymal transition (EMT), which is characterized by increased E-cadherin expression and decreased vimentin, N-cadherin and Slug expression. Interleukin 6 (IL-6), a pro-inflammatory cytokine produced mainly by macrophages, could promote cancer cell EMT and invasion. In contrast, treatment with QYHJ inhibited cancer-related inflammation in tumors by decreasing infiltration of tumor-associated macrophages and IL-6 production, thus preventing cell invasion and metastasis. These results suggested that the Chinese herbal medicine QYHJ could inhibit pancreatic cancer cell invasion and metastasis in part by reversing tumor-supporting inflammation.
PLoS ONE 01/2013; 8(7):e70334. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway.
[Show abstract][Hide abstract] ABSTRACT: Background. METHODS: Some studies suggest that acupuncture may be beneficial. Objectives. The authors evaluated the preventive and therapeutic effect of acupuncture for radiation-induced xerostomia among patients with head and neck cancer. Methods. PUBMED, EMBASE, Cochrane Library, CBM, CAJD, Wan Fang database, and VIP Database for Chinese Technical Periodicals were electronically searched, in conjunction with further manual search for relevant articles. Studies that met the inclusion criteria were systematically evaluated. RESULTS: Three randomized controlled trials (RCTs) investigating the therapeutic effect of acupuncture were included. One RCT on the preventive effect of acupuncture was found. Because of the considerable variation among included studies, meta-analysis was not possible. Two included RCTs used placebo controls, and both observed significant improvement in the salivary flow rates between acupuncture and control groups. However, no significant differences were found. Three included RCTs suggested that acupuncture for radiation-induced xerostomia can improve patients' subjective symptoms. The only study evaluating the preventive effect of acupuncture for radiation-induced xerostomia showed positive changes in salivary flow rates (both unstimulated and stimulated) and dry mouth -related symptoms. Acupuncture treatment was well tolerated by all patients and no severe adverse effects were seen. CONCLUSIONS: Insufficient evidence is available to judge whether acupuncture is safe and whether it is effective in preventing or treating radiation-induced xerostomia. Significant research remains to be done before acupuncture can be recommended for routine use in radiation-induced xerostomia.
Integrative Cancer Therapies 07/2012; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients. Quality of life (QOL) is impaired, and available treatments are of little benefit. This trial determined the feasibility of conducting a sham-controlled trial of acupuncture and whether acupuncture could prevent xerostomia among head/neck patients undergoing radiotherapy.
A sham controlled, feasibility trial was conducted at Fudan University Shanghai Cancer Center, Shanghai, China among patients with nasopharyngeal carcinoma undergoing radiotherapy. To determine feasibility of a sham procedure, 23 patients were randomised to real acupuncture (N=11) or to sham acupuncture (N=12). Patients were treated three times/week during the course of radiotherapy. Subjective measures were the Xerostomia Questionnaire (XQ) and MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN). Objective measures were unstimulated whole salivary flow rates (UWSFR) and stimulated salivary flow rates (SSFR). Patients were followed for 1 month after radiotherapy.
XQ scores for acupuncture were significantly lower than sham controls starting in week 3 and lasted through the 1-month follow-up (all P's <0.001 except for week 3, which was 0.006), with clinically significant differences as follows: week 6 - RR 0.28 [95% confidence interval, 0.10, 0.79]; week 11 - RR 0.17 [95%CI, 0.03, 1.07]. Similar findings were seen for MDASI-HN scores and MDASI-Intrusion scores. Group differences for UWSFR and SSFR were not found.
In this small pilot study, true acupuncture given concurrently with radiotherapy significantly reduced xerostomia symptoms and improved QOL when compared with sham acupuncture. Large-scale, multi-centre, randomised and placebo-controlled trials are now needed.
European journal of cancer (Oxford, England: 1990) 01/2012; 48(11):1692-9. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In our previous study, the mouse double minute 2 (MDM2) was identified as one of the leading genes that promote the metastasis of pancreatic cancer (PC). However, the mechanism by which MDM2 promotes metastasis of PC is not understood. In this study, we show that down-regulation of MDM2 through lentivirus-mediated RNA interference could also suppress in vitro proliferation and in vivo tumor growth, and led to an obvious inhibition of both in vitro invasion and in vivo live metastases of SW1990HM cells which had an over-expression of MDM2 and a higher metastatic potential. Moreover, we also show that the down-regulation of MDM2 induced a significant decrease in MMP9, Ki-67 and increase in P53, E-Cadherin expression, and results in an altered expression of genes involved in metastasis, apoptosis, and cell proliferation. Our results suggest that MDM2 plays an important role in metastasis as well as tumor growth of PC. MDM2 could be a hopeful target for the control of PC.
Molecular and Cellular Biochemistry 12/2011; · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients, and available treatments are of little benefit. The objective of this trial was to determine whether acupuncture can prevent xerostomia among head/neck patients undergoing radiotherapy.
A randomized, controlled trial among patients with nasopharyngeal carcinoma was conducted comparing acupuncture to standard care. Participants were treated at Fudan University Shanghai Cancer Center, Shanghai, China. Forty patients were randomized to acupuncture treatment and 46 to standard care. Patients were treated 3×/wk on the same days they received radiotherapy. Subjective measures included the Xerostomia Questionnaire and MD Anderson Symptom Inventory-Head and Neck (MDASI-HN). Objective measures were unstimulated and stimulated whole salivary flow rates. Patients were followed for 6 months after the end of radiotherapy.
Xerostomia Questionnaire scores for acupuncture were statistically significantly lower than for controls starting in week 3 through the 6 months (P = .003 at week 3, all other P < .0001), with clinically significant differences as follows: week 11, relative risk (RR) 0.63 (95% confidence interval [CI], 0.45-0.87); 6 months, RR 0.38 (95% CI, 0.19-0.76). Similar findings were seen for MDASI-HN scores. Group differences emerged as early as 3 weeks into treatment for saliva (unstimulated whole salivary flow rate, P = .0004), with greater saliva flow in the acupuncture group at week 7 (unstimulated whole salivary flow rate, P < .0001; stimulated whole salivary flow rate, P = .002) and 11 (unstimulated whole salivary flow rate, P < .02; stimulated whole salivary flow rate, P < .03) and at 6 months (stimulated whole salivary flow rate, P < .003).
Acupuncture given concurrently with radiotherapy significantly reduced xerostomia and improved quality of life.
Cancer 11/2011; 118(13):3337-44. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bufalin, a major bioactive component of the Chinese medicine Chansu, has been reported to exhibit significant antitumor activity against various cancer cell lines. However, the exact mechanism remains unclear. In this study, we demonstrated that bufalin inhibited the growth of hepatocellular carcinoma (HCC) cells in a dose-dependent manner, which correlated with the expression level of Na+/K+-ATPase α3 in HCC cells. The IC50 of bufalin markedly increased when Na+/K+-ATPase α3 was silenced by RNA interference. Furthermore, we show that bufalin increased the phosphorylation of Akt and ERK1/2 while inhibited FoxO3a expression. Thus, our study suggests that Na+/K+-ATPase α3 might serve as a therapeutic target for bufalin in HCC, and its expression status may help predict sensitivity of HCC cells to bufalin treatment.
[Show abstract][Hide abstract] ABSTRACT: To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM).
From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed.
Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (>10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors.
Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the pain-alleviating action, feasibility and efficacy of high intensity focused ultrasound (HIFU) for palliation of inoperable pancreatic cancer in humans.
Forty patients with advanced pancreatic cancer were treated with HIFU. There were 13 patients with stage III, and 27 patients with stage IV disease. The locations of the tumours were as follows: head of pancreas in 9 patients, body and/or tail of pancreas in 31 patients. Pain relief, local tumour control rate, median survival and complications were monitored after HIFU treatment. The primary endpoint was to assess pain relief rate and pain relief time (PRT). Secondary endpoints included local progression-free survival time, overall survival (OS), and side effects.
There were no severe complications or adverse events related to HIFU therapy in any of the patients treated. Pain relief was achieved in 87.5% of patients, median PRT was 10 weeks. The median local progression-free survival time for all patients was 5 months. The median overall survival time was 10 months for patients with stage III disease, and 6 months for patients with stage IV disease. The median OS time, 6-month and 1-year survival rate for patients as a whole were 8 months, 58.8% and 30.1%, respectively.
Although this study may have limitations, preliminary results demonstrate the safety of clinical application of HIFU for pancreatic cancer and reveal it to be a promising mode of treatment for palliation of pain associated with pancreatic cancers.
International Journal of Hyperthermia 01/2011; 27(2):101-7. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibody microarrays have been successfully used to determine relative abundance of key proteins in various cancers and other diseases. We have previously showed liver metastatic-related genes between the metastatic pancreatic cancer line (SW1990HM) and its parental line (SW1990). In this study, we searched for potential markers for metastatic progression using antibody microarrays. The SpringBio Antibody Microarrays were used to analysis the different proteomes between SW1990HM and SW1990 cells. A standard ≥2.0-fold cutoff value was used to determine differentially expressed proteins and Western blotting analysis further confirmed the results. Antibody microarrays revealed that 40 proteins were reproducibly altered more than 2-fold between the selected variant and its parental counterpart; 14 of the proteins were up-regulated, and 26 were down-regulated. Most of the up-regulated proteins (7/14) play a role in tumor signal transduction, while a number of down-regulated proteins (10/26) function in cell differentiation; this might be crucial for pancreatic cancer metastasis. Four dysregulated proteins were validated by western blotting in the cell lines. Interestingly, the up-regulation of Glucagon and down-regulation of Prolactin were further confirmed in the culture supernatants by western blotting. These proteomic data are valuable for understanding pancreatic cancer metastasis and searching for potential markers of metastatic progression.
Molecular and Cellular Biochemistry 10/2010; 347(1-2):117-25. · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Huachansu, a Chinese medicine that comes from dried toad venom from the skin glands of Bufo gargarizans or B. melanostictus, has been used in the treatment of various cancers in China. The authors conducted a pilot study, using a phase 1 trial design, of huachansu in patients with advanced cancer.
Huachansu was administered intravenously for 14 days followed by 7 days off (1 cycle). Without significant adverse events or progressive disease, treatment continued beyond 2 cycles. The dose of huachansu was escalated as follows with 3 patients per cohort: 10 (level 1), 20 (level 2), 40 (level 3), 60 (level 4), and 90 (level 5) mL/m(2).
Fifteen patients (hepatocellular cancer, n = 11; nonsmall cell lung cancer, n = 2; pancreatic cancer, n = 2) were enrolled in the trial, and no dose-limiting toxicities (DLTs) were found. Eleven patients had no drug-related toxicity greater than grade 1. Six (40%) had stable disease (median duration, 6.0 months; range, 3.5-11.1 months). One of these patients (with hepatocellular cancer) had 20% regression (duration, 11 months) (dose level 1). Quality of life improved for patients with stable disease. Plasma bufalin concentration reached maximal levels at the end of the 2-hour infusion and was proportional to the amount of drug being administered (0.81-3.38 ng/mL).
No DLT was observed with the use of huachansu at doses up to 8x higher than typically used in China. Six patients had prolonged stable disease or minor tumor shrinkage.
Cancer 09/2009; 115(22):5309-18. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate and compare the effects and toxicity of the domestic product of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy and chemotherapy alone in the treatment of patients with non-small cell lung cancer (NSCLC).
Two hundred patients with NSCLC in multicenter were randomly devided into trial group (150 cases) and control group (50 cases). Chemotherapy with CAP regimen was given to the patients. Meanwhile, rmhTNF injection of 4×10⁶U/m² was also given from the 1st to 7th days, the 11th to 17th days on the chemotherapy cycle in the trial group. The control patients received chemotherapy alone. Twenty-one days were as a cycle, 2 cycles were given to each patient. The chemotherapeutic effects and toxicity were observed and compared between the two groups after the therapy.
of the 200 patients, 5 cases in the trial group and 3 cases in the control group were out of the trial because of economy. The other 192 cases (145 cases in the trial group and 47 cases in the control group) could be analyzed and evaluated the clinical effects and toxicity. The response rate of chemotherapy was 46.90% (68/145) in the trial group and 17.02% (8/47) in the control group respectively ( P =0.001). The KPS scores was 86.02±9.74 in the trial group, and 80.14±9.10 in the control group ( P =0.025). No significant difference of degree III+IV toxicity was observed between the two groups ( P > 0.05). The side effects related to rmhTNF included slight fever, cold-like symptoms, pain and red and swelling in the injection site. All of them were mild and didn't need any treatment and disappeared after the therapy. There were no severe abnormality of liver and kidney function and ECG in both groups.
The results demonstrate that the effects of domestic rmhTNF combined with chemotherapy are remarkably higher than that of chemotherapy alone in the treatment of NSCLC. rmhTNF can increase the sensitivity to chemotherapy and improve the quality of life of the patients with slight toxicity. Hence rmhTNF is worth expanding clinical use.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 08/2003; 6(4):264-7.
[Show abstract][Hide abstract] ABSTRACT: Resibufogenin and cinobufagin are the major bioactive constituents in the Chinese medicine Ch’an Su. In this paper, a novel,
simple and rapid method was developed for the qualitative analysis of the two main compounds, which was based on microwave-assisted
silylation followed by gas chromatography–mass spectrometry. The components of resibufogenin and cinobufagin were derivatized
with N,O-bis(trimethylsilyl)trifluoroacetamide under microwave irradiation, and the trimethylsilyl derivatives formed were analyzed
by GC–MS. The derivatization conditions including microwave power and irradiation time were investigated, and the method validations
(linear range, detection limit, precision and recovery) were also studied. The experimental results indicate that microwave-assisted
silylation followed by GC–MS analysis is a new method for the determination of resibufogenin and cinobufagin in the Ch’an