X-ray inhibits FUT4-mediated proliferation in A549 cells by downregulating SP1 expression.

Objective: To identify the mechanism of down-regulation of Lewis Y antigen caused by X-ray irradiation. METHODS: The present original research study was conducted at Zhejiang University City College, Hangzhou, Republic of China, from 2020 to 2022. Western blotting, Co-immunoprecipitation (CO-IP), electrophoretic mobility shift assay and Cell Counting Kit-8 (CCK8) were performed to confirm the effect of X-ray irradiation on A549 cell proliferation and its mechanism. Data was analysed using Statistical Package for Social Sciences (SPSS) 11.5. RESULTS: The expressions of fucosyltransferase IV and Lewis Y were decreased after X-ray irradiation, thus inhibiting the proliferation of A549 lung cancer cells. Deoxyribonucleic acid damage caused by the irradiation caused higher level of poly- adenosinediphosphate-ribosylated Specific Protein 1(SP1), and translocation of SP1 from the nucleus, decreasing the expression of fucosyltransferase IV and Lewis Y. Conclusion: There was a significant role of glycosylation in radiation therapy for lung cancer.

Emodin reverses resistance to gemcitabine in pancreatic cancer by suppressing stemness through regulation of the epithelial­mesenchymal transition.

The present study aimed to explore the effects and underlying mechanisms of emodin (Emo) on gemcitabine (GEM)-resistant pancreatic cancer. GEM-resistant SW1990 cells (SW1990/GZ) were established by successively doubling the concentration of GEM. Cell viability was measured using the CCK-8 assay and flow cytometry was used to measure cell apoptosis. Cell migration was assessed using a Transwell assay. Sphere and colony-formation assays were used to evaluate cell self-renewal. The expression levels of epithelial-mesenchymal transition (EMT) and stem cell biomarkers were determined using western blotting. Snail family transcriptional repressor 1 gene (Snail) was overexpressed by transfecting cells with pcDNA3.1-Snail plasmids. A xenograft model was established in nude mice by using SW1990/GZ and Snail-overexpressing SW1990/GZ cells. Proliferation, migration, self-renewal and EMT progression of GEM-treated SW1990/GZ cells were significantly suppressed in vitro by Emo treatment, whereas the overexpression of Snail abolished the aforementioned effects. In in vivo, the antitumor activity of GEM and the inhibitory effect of GEM against EMT progression and stem-like characteristics were enhanced by treatment with Emo, whilst overexpression of Snail reversed these effects. In conclusion, Emo reversed GEM resistance in pancreatic cancer by suppressing stemness and regulating EMT progression.

Effects of pre-operative enteral immunonutrition for esophageal cancer patients treated with neoadjuvant chemoradiotherapy: protocol for a multicenter randomized controlled trial (point trial, pre-operative immunonutrition therapy).

BACKGROUND: Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. METHODS: POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. DISCUSSION: This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www. CLINICALTRIALS: gov/ct2/show/NCT04513418 .

MiR-199 Reverses the Resistance to Gemcitabine in Pancreatic Cancer by Suppressing Stemness through Regulating the Epithelial-Mesenchymal Transition.

PURPOSE: the present study aims to investigate the function of miR-199 on gemcitabine (GEM)-resistance in pancreatic cancer, as well as the underlying mechanism. METHODS: the GEM-resistant SW1990 cell line (SW1990/SZ) was established. The CCK-8 assay was used to detect the cell viability. The self-renewal of SW1990/SZ cells was evaluated by sphere formation and the colony formation assay. The apoptosis was detected by flow cytometry and the migration ability was measured by the transwell assay. The dual-luciferase gene reporter assay was utilized to confirm the binding between miR-199 and Snail. The expression level of CD44, ALDH1, Nanog, E-cadherin, Vimentin, ß-catenin, and Snail was determined by the Western blotting assay. RESULTS: the cell sphere formation rate, number of spheres, and expression level of CD44, ALDH1, and Nanog in GEM-treated SW1990/SZ cells were significantly suppressed by miR-199, accompanied by declined proliferation ability, an increased apoptotic rate, inhibited migration ability, and suppressed EMT progression. The binding site between miR-199 and 3'-UTR of Snail was predicted and confirmed. The inhibitory effect of miR-199 on self-renewal of SW1990/GZ cells and the faciliating property of miR-199 on the inhibitory effect of GEM against the proliferation ability, migration ability, and EMT progression were abolished by overexpressing Snail. CONCLUSION: MiR-199 reversed the resistance to GEM in pancreatic cancer by suppressing stemness through regulating the EMT.

Anticancer mechanism of breviscapine in non-small cell lung cancer A549 cells acts via ROS-mediated upregulation of IGFBP4.

BACKGROUND: The overall 5-year survival rate of non-small cell lung cancer (NSCLC) is less than 15% because of multiple drug resistance to chemotherapy and the limitations of early diagnosis. Thus, safe and effective drugs to treat NSCLC are required. The present study aimed to investigate the effects of breviscapine (BVP) on NSCLC cell apoptosis and proliferation, and to study its possible mechanisms. METHODS: Using the NSCLC A549 cell line and BVP (0, 25, 50, and 100 µM), the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect A549 cell proliferation, and flow cytometry was used to assess cell apoptosis. Insulin-like growth factor binding protein 4 (IGFBP4) levels was assessed using enzyme-linked immunosorbent assays and western blotting. Flow cytometry of hydrogen peroxide and superoxide was used to assess intracellular reactive oxygen species (ROS) generation. Western blotting was used to assess the levels of BCL2-associated X, apoptosis regulator (BAX) and B-cell CLL/lymphoma 2 (BCL2). Quantitative real-time reverse transcription PCR (qRT-PCR) was used to assess IGFBP4 mRNA expression. RESULTS: BVP induced apoptosis, inhibited cell proliferation, and increased ROS in A549 cells. Western blotting and qRT-PCR showed that BVP increased IGFBP4 protein and mRNA expressions in A549 cells. Compared with BVP treatment alone, IGFBP4 expression decreased in A549 cells treated with BVP and the ROS scavenger N-acetylcysteine. IGFBP4 overexpression increased BVP-induced proliferation inhibition, while increasing BAX expression and decreasing BCL2 expression. Silencing IGFBP4 had the opposite effects. CONCLUSIONS: BVP could inhibit the growth of NSCLC A549 cells by promoting apoptosis via ROS-mediated upregulation of IGFBP4.

Molecular Analysis of Oncogenic Mutations in Resected Margins by Next-Generation Sequencing Predicts Relapse in Non-Small Cell Lung Cancer Patients.

OBJECTIVE: To investigate the genetic mutations in both tumor and marginal tissues in patients with non-small cell lung cancer (NSCLC), and to evaluate the potential prognostic value in patients with margins gene positive. METHODS: Next-generation sequencing (NGS) technique was used to detect genetic mutation in tumor and marginal tissues of the bronchus in 88 patients with NSCLC. Correlation of genetic mutations with pathology, lymph node metastasis, disease-free survival and overall survival was analyzed. RESULTS: Of the 88 patients, 83 cases (94.3%) had gene mutations in the tumor samples and 12 cases (13.6%) had genetic alterations in their margins. Most of the gene mutations detected were cancer drivers. Six common driver genes between tumor and marginal tissues were identified, including EGFR, TP53, CDKN2A, CTNNB1, BRAF, and NF1. Kaplan-Meier analysis revealed that the median disease-free survival (DFS) was significantly shorter in patients with detectable gene mutations in marginal tissues compared with patients without mutations in margins (30.7 versus 24.4 months, log-rank χ 2 = 4.78, P =0.029). Consistently, a shorter median OS was observed in patients harboring gene mutations in margins compared with patients with no mutations in margins (49.1 versus 32.2 months, log-rank χ 2 = 3.669, P =0.055). CONCLUSION: These findings identify the presence of oncogenic alterations in microscopically negative margins in NSCLC patients associated with elevated risk of relapse and shorter survival time. Thus, examination of microscopically negative margins by NGS represents a valuable approach to predict the clinical outcome of NSCLC patients.

LncRNA EIF3J-AS1 enhanced esophageal cancer invasion via regulating AKT1 expression through sponging miR-373-3p.

Esophageal cancer (ECa) remains a major cause of mortality across the globe. The expression of EIF3J-AS1 is altered in a plethora of tumors, but its role in ECa development and progression are undefined. Here, we show that EIF3J-AS1 is up-regulated in ECa and that its expression correlates with advanced TNM stage (P = 0.014), invasion depth (P = 0.001), positive lymph node metastasis (P < 0.001) and poor survival (OS: P = 0.0059; DFS: P = 0.0037) in ECa. Functional experiments showed that knockdown EIF3J-AS1 inhibited ECa growth and metastasis through in vitro and in vivo experiments. Regarding the mechanism, EIF3J-AS1/miR-373-3p/AKT1 established the ceRNA network involved in the modulation of cell progression of ECa cells. Overall, EIF3J-AS1 may exhibit an oncogenic function in ECa via acting as a sponge for miR-373-3p to up-regulate AKT1 mRNA level, and may serve as a potential therapeutic target and a prognostic biomarker for ECa patients.

Benign metastasizing leiomyoma of the lung: A case report and literature review.

Pulmonary benign metastasizing leiomyoma (BML) is a rare event characterized by benign soft-tissue tumors that occur when uterine leiomyomas metastasize to the lung. The present study reports the case of a 47-year-old female patient who presented with multiple bilateral pulmonary nodules on a chest X-ray during a health checkup nine years after a hysterectomy due to uterine fibroids. Chest computed tomography (CT) revealed multiple well-defined nodular shadows in the lung. One tumor of the left upper lung was resected by thoracoscopic surgery. Pathologically, the resected lesion consisted of benign spindle cells and was diagnosed as BML. The post-operative course was uneventful. Other lung nodules have been meticulously monitored at follow-up, and repeat CT two years later showed that these nodules had not increased at all in size and that no new lobe nodules had appeared. The present study indicates that pulmonary BML occurs in a low proportion of female with a history of uterine leiomyoma and treatment methods for it are diverse and controversial.

Oridonin induces apoptosis in SW1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 MAPK.

Oridonin, an active component isolated from Rabdosia rubescens, has been reported to exhibit antitumor effects. In the present study, we evaluated the antitumor activity and the mechanisms of action of oridonin in pancreatic cancer. Oridonin treatment significantly induced apoptotic cell death in SW1990 pancreatic cancer cells in a dose-dependent manner. Additionally, cell apoptosis was markedly inhibited by PFT α (pifithrin α), a p53-specific inhibitor, which was applied to evaluate the function of p53, showing that p53 was responsible for the cytotoxity of oridonin. Moreover, oridonin increased the expression of p-p53 with a concomitant increase in p21 in the SW1990 cells. Following treatment with mitogen-activated protein kinase (MAPK) inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor), the cytotoxity of oridonin was not influenced by JNK (SP600125) and ERK (PD98059), but these effects were opposite to the cytotoxity of oridonin observed with SP203580 treatment. These findings confirmed that orodonin-induced apoptosis was p38-dependent, but JNK- and ERK-independent. Furthermore, the activation of the p38 kinase promoted the activation of p53 and its downstream target p21, and further caused caspase-9 and -3 activation, as demonstrated by evidence showing that the p38 inhibitor SB203580 not only blocked the phosphorylation of p38 but also reduced the activation of p53, p21 and caspase-9 and -3. Collectively, these results suggest that p53-dependent and caspase-dependent induction of p38 MAPK directly participates in apoptosis induced by oridonin.

The distinct mechanisms of the antitumor activity of emodin in different types of cancer (Review).

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. The inhibitory effect of emodin on mammalian cell cycle modulation in specific oncogene-overexpressing cells has formed the basis for using this compound as an anticancer drug. Previous reviews have summarized the antitumor properties of emodin. However, the specific molecular mechanisms of emodin-mediated tumor inhibition have not been completely elucidated over the last 5 years. Recently, there has been great progress in the preclinical study of the anticancer mechanisms of emodin. Our recent study revealed that emodin has therapeutic effects on pancreatic cancer through various antitumor mechanisms. Notably, the therapeutic efficacy of emodin in combination with chemotherapy was found to be higher than the comparable single chemotherapeutic regime, and the combination therapy also exhibited fewer side-effects. Despite these encouraging results, further investigation is warranted as emodin has been shown to modulate one or more key regulators of cancer growth. This review provides an overview of the distinct mechanisms of anticancer action of emodin in different body systems identified over the past 5 years. These new breakthrough findings may have important implications for targeted cancer therapy and for the future clinical use of emodin.

Risk factors for No. 12p and No. 12b lymph node metastases in advanced gastric cancer in China.

BACKGROUND: The risk factors for No. 12p and No. 12b lymph node (LN) metastases in advanced gastric cancer (GC) remain controversial. The aim of this study was to investigate the risk factors for No. 12p and No. 12b LN metastases in advanced GC. METHODS: From January 1999 to December 2005, a retrospective analysis of 163 patients with advanced GC who underwent D2 lymphadenectomy in addition to No. 12p and No. 12b LN dissections was conducted. Potential clinicopathological factors that could influence No. 12p and No. 12b LN metastases were statistically analyzed. RESULTS: There were 15 cases (9.2%) with No. 12p LN metastases and 5 cases (3.1%) with synchronous No. 12b LN metastases. A logistic regression analysis revealed that the Borrmann type (III/IV versus I/II, P = 0.029), localization (lesser/circular versus greater, P = 0.025), and depth of invasion (pT4 versus pT2/pT3, P = 0.009) were associated with 11.1-, 3.8-, and 5.6-fold increases, respectively, for risk of No. 12p and No. 12b LN metastases. A logistic regression analysis also showed that No. 5 (P = 0.006) and No. 12a (P = 0.004) LN metastases were associated with 6.9- and 11.3-fold increases, respectively, for risk of No. 12p and No. 12b LN metastases. In addition, significant differences in 5-year survival of patients with and without No. 12p and No. 12b LN metastases were observed (13.3% versus 35.1%, P = 0.022). CONCLUSION: We conclude that Borrmann type, localization, and depth of invasion are significant variables for identifying patients with No. 12p and No. 12b LN metastases. Individuals with No. 5 or No. 12a LN metastases should be on high alert for the possibility of additional metastases to the No. 12p and No. 12b LNs.

Antitumor activity of emodin against pancreatic cancer depends on its dual role: promotion of apoptosis and suppression of angiogenesis.

BACKGROUND: Emodin has been showed to induce apoptosis of pancreatic cancer cells and inhibit tumor growth in our previous studies. This study was designed to investigate whether emodin could inhibit the angiogenesis of pancreatic cancer tissues and its mechanism. METHODOLOGY/PRINCIPAL FINDING: In accordance with our previous study, emodin inhibited pancreatic cancer cell growth, induced apoptosis, and enhanced the anti-tumor effect of gemcitabine on pancreatic caner cells in vitro and in vivo by inhibiting the activity of NF-κB. Here, for the first time, we demonstrated that emodin inhibited tumor angiogenesis in vitro and in implanted pancreatic cancer tissues, decreased the expression of angiogenesis-associated factors (NF-κB and its regulated factors VEGF, MMP-2, MMP-9, and eNOS), and reduced eNOS phosphorylation, as evidenced by both immunohistochemistry and western blot analysis of implanted tumors. In addition, we found that emodin had no effect on VEGFR expression in vivo. CONCLUSIONS/SIGNIFICANCE: Our results suggested that emodin has potential anti-tumor effect on pancreatic cancer via its dual role in the promotion of apoptosis and suppression of angiogenesis, probably through regulating the expression of NF-κB and NF-κB-regulated angiogenesis-associated factors.

Emodin potentiates the antitumor effects of gemcitabine in PANC-1 pancreatic cancer xenograft model in vivo via inhibition of inhibitors of apoptosis.

Pancreatic cancer is a highly aggressive malignant disease. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. As members of apoptosis inhibitors, Survivin and XIAP play an important role in chemotherapy resistance in pancreatic cancer. Emodin has therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and emodin enhanced antitumor efficacy in pancreatic cancer. The application of the combination therapy triggered significantly higher frequency of pancreatic cancer cell apoptosis. Our research demonstrated that the combination of emodin and gemcitabine resulted in significantly reduced tumor volumes compared to gemcitabine or emodin treatment alone. Immunohistochemistry and western immunoblot analyses showed that Survivin and XIAP expression were downregulated in emodin and the combination groups compared to the other two groups. Reverse transcriptase polymerase chain reaction analyses showed that Survivin and XIAP mRNA expression in emodin and the combination groups were downregulated significantly compared to the other two groups. Furthermore, the expression of the nuclear transcription factor κB (NF-κB) protein and NF-κB mRNA were downregulated in the emodin and the combination groups. DNA-binding activity of NF-κB was inhibited in emodin and combination groups compared to the other groups. This study suggests that emodin potentiates the antitumor effects of gemcitabine in PANC-1 cell xenografts via promotion of apoptosis and IAP suppression.

Enhanced antitumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway.

Evodiamine has therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and evodiamine enhanced antitumor efficacy in pancreatic cancer. In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-κB and expression of NF-κB-regulated products. In vivo application of the combination therapy induced significant enhancement of tumor cell apoptosis, reductions in tumor volume, and inhibited activation of mTOR and PTEN. In conclusion, evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway.

Antitumor and apoptosis-promoting properties of emodin, an anthraquinone derivative from Rheum officinale Baill, against pancreatic cancer in mice via inhibition of Akt activation.

Pancreatic adenocarcinoma is one of the most common malignancies worldwide. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine can induce activation of Akt and nuclear factor-κB (NF-κB), which is associated with its chemoresistance. It has been reported that gemcitabine combination therapies result in improved survival outcomes in pancreatic cancer. Therefore, agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Emodin is an active component of Chinese medicinal herbs and can inhibit the activation of Akt and NF-κB. In this study, we investigated whether emodin could enhance the anticancer effect of gemcitabine on pancreatic cancer in vivo. We demonstrated that treatment of gemcitabine combined with emodin efficiently suppressed tumor growth in mice inoculated with pancreatic tumor cells. This treatment paradigm promoted apoptotic cell death and mitochondrial fragmentation. Furthermore, it reduced phosphorylated-Akt (p-Akt) level, NF-κB activation and Bcl-2/Bax ratio, increased caspase-9 and -3 activation, Cytochrome C (CytC) release occurred in combination therapy. Collectively, emodin enhanced the activity of gemcitabine in tumor growth suppression via inhibition of Akt and NF-κB activation, thus promoting the mitochondrial-dependent apoptotic pathway. Therefore, our findings may provide new insights into understanding the pharmacological regulation of emodin on gemcitabine-mediated proapoptosis in pancreatic cancer and may aid in the design of new therapeutic strategies for the intervention of human pancreatic cancers.

Enhanced antitumor efficacy by the combination of emodin and gemcitabine against human pancreatic cancer cells via downregulation of the expression of XIAP in vitro and in vivo.

XIAP and NF-κB play an important role in chemotherapy resistance in pancreatic cancer. The purpose of this study was to explore the role of XIAP and NF-κB in potentiating the antitumor effect of gemcitabine by emodin in pancreatic cancer. SW1990 cells were treated by sodium chloride, gemcitabine, emodin or their combination (gemcitabine plus emodin). Cellular proliferation and apoptosis were detected by Cell Counting kit-8 (CCK-8) assay and flow cytometry in vitro. The combination therapy more significantly inhibited SW1990 cell growth and induced a higher percentage of apoptosis than monotherapy. Gemcitabine upregulated the expression of XIAP and NF-κB, while emodin or emodin plus gemcitabine downregulated them compared to the control group in vitro. SW1990 cells were used to establish orthotopic pancreatic tumor models in nude mice. Tumor-bearing mice were treated with sodium chloride, emodin, gemcitabine or their combination. After being treated for 4 weeks, the nude mice were imaged with high-resolution positron emission tomography (microPET) and fluorine-18-labeled fluorodeoxyglucose (18F-FDG) to detect the tumor/non-tumor ratio (T/NT ratio) and standard uptake value (SUV). The mice were sacrificed to determine tumor weight. The combination of emodin and gemcitabine showed more significant reduction in the T/NT ratio, SUV and tumor weight compared to monotherapy. The mRNA levels and the protein expression of XIAP and NF-κB were upregulated in the gemcitabine group, while they were downregulated in the emodin group and the combination group in vivo. Ki-67 prolif-eration index and TUNEL assay results also showed that emodin enhanced tumor apoptosis induced by gemcitabine in vivo. This study suggests that emodin enhances the antitumor effect of gemcitabine in SW1990 pancreatic cancer in vitro and in vivo, which may be via the downregulation of NF-κB expression, thus inhibiting the expression of XIAP.

Antiproliferative and antimetastatic effects of emodin on human pancreatic cancer.

Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone) is an active constituent isolated from the root of Rheum palmatum L and is the main effective component of some Chinese herbs and plants. Pharmacological studies have demonstrated that emodin exhibits anti-cancer effects on several human cancers. However, the molecular mechanisms of emodin-mediated tumor regression have not been fully defined. This study was performed to investigate the antiproliferative and antimetastatic effects of emodin on pancreatic cancer in vitro and in vivo. Our results showed that emodin induced a higher percentage of growth inhibition and apoptosis in the pancreatic cancer cell line SW1990 compared to that of control, and emodin suppressed the migration and invasion of SW1990 cells in a dose-dependent manner. To investigate the possible mechanisms involved in these events, we performed electrophoretic mobility shift assay (EMSA) and Western blot analysis, and found that emodin significantly down-regulated NF-κB DNA-binding activity, survivin and MMP-9 in SW1990 cells. Moreover, the expression of cleaved caspase-3 was up-regulated in SW1990 cells after treatment with emodin. In addition, a metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into the pancreatic wall of nude mice. Oral administration of emodin significantly decreased tumor weight and metastasis compared to control. Furthermore, the expression of NF-κB, survivin and MMP-9 were also suppressed in tumor tissues after treatment with emodin. Collectively, our results indicated that emodin exerts antiproliferative and antimetastatic activity on pancreatic cancer both in vitro and in vivo, which may be related to down-regulation of NF-κB and its regulated molecules such as survivin and MMP-9 proteins. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human pancreatic cancer.

Enhanced effect of gemcitabine by emodin against pancreatic cancer in vivo via cytochrome C-regulated apoptosis.

Gemcitabine is currently the best treatment available for pancreatic cancer, but causes high toxicity. Agents that can enhance the effects of gemcitabine with no or low toxicity are needed for the treatment of pancreatic cancer. Emodin, a natural anthraquinone derivative, is one such agent that has been shown to induce apoptosis in other tumor cells via down-regulation of Bcl-2/Bax and promoting the release of Cytochrome C (CytC), but with very low toxicity. The aim of this study was to evaluate whether emodin can enhance the effect of gemcitabine on pancreatic cancer in vitro and in vivo and to investigate the possible mechanisms of the enhancement. In vitro, emodin inhibited the proliferation of the SW1990 cell line and potentiated the apoptosis induced by gemcitabine, which was demonstrated by activation of caspase-3 in the combination group. In vivo, tumors from nude mice subcutaneously injected with SW1990 cells and treated with a combination of emodin (40 mg/kg) and gemcitabine (80 mg/kg) showed significant reductions in volume, Ki-67 proliferation index and expression of the Bcl-2/Bax ratio (compared with tumors from mice treated with sodium chloride, emodin alone (40 mg/kg) or gemcitabine alone (125 mg/kg), which induced increasing release of CytC from the mitochondria to the cytoplasm and triggered caspase-3 activation leading to apoptosis. Taken together, our results suggest that emodin improved the anti-tumor effect of gemcitabine, even at a lower dose of gemcitabine which could decrease the toxicity of chemotherapy, on transplanted tumors of the SW1990 cell line through the enhancement of apoptosis induced by gemcitabine, the mechanism of which may be through down-regulation of the Bcl-2/Bax ratio and promoting release of CytC from the mitochondria into the cytoplasm.

[Emodin enhances antitumor effect of gemcitabine in model of SW1990 cell xenograft on athymic mouse].

OBJECTIVE: To evaluate the enhanced effect of gemcitabine by emodin and the possible mechanisms of the enhancement. METHOD: Based on the model of SW1990 cell xenograft on athymic mouse, the mice were randomized to four groups with intraperitoneal (IP) injections of different drugs: group N (injecting 0.9% sodium chloride), group E (emodin, 40 mg x kg(-1)), group G (gemcitabine, 125 mg x kg(-1)), and group E + G (emodin 40 mg x kg(-1) and gemcitabine 80 mg x kg(-1) in combination). The tumor volume, tumor weight and body weight of mice were measured during the drug therapy. The mice were sacrificed one week after last injection of drug. Tunel assay were used used to detect the apoptosis of tumor cells. And immunohistochemistry (IHC) and Western blot (WB) were used to detect the variance of the apoptosis relative protein expression of Bax, Bcl-2, and Cytochrome C . RESULT: One week after the last administration, the mean tumor volume and tumor weight in group E + G were significantly decreased compared to the other groups. Tunel assay showed group E + G presented apparently more apoptosis than the other groups. Immunohistochemistry (IHC) and Western blot (WB) analysis showed the expression of Cytochrome C in cytoplasmin and Bax in group E + G was apparently upregulated while the expression of Bcl-2 was apparently downregulated compared to the other groups. As a result, Bcl-2/Bax ratio was significantly decreased in group E + G. CONCLUSION: Emodin can significantly improve the antitumor effect of gemcitabine on transplanted tumor of SW1990 cell line through apparently enhancing the tumor cell apoptosis by gemcitabine. Downregulation of Bcl-2/Bax ratio and promoting release of Cytochrome C from mitochondria is possibly one of the mechanisms of the augmented apoptosis.