Bufalin Inhibits Tumorigenesis and SREBP-1-Mediated Lipogenesis in Hepatocellular Carcinoma via Modulating the ATP1A1/CA2 Axis.

Altered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.

Magnesium transporter protein solute carrier family 41 member 1 suppresses human pancreatic ductal adenocarcinoma through magnesium-dependent Akt/mTOR inhibition and bax-associated mitochondrial apoptosis.

The aim of this study was to identify the function of the Mg2+ transporter protein solute carrier family 41 member 1 SLC41A1 in pancreatic ductal adenocarcinoma and the underlying mechanisms. A total of 27 solute carrier proteins were differentially expressed in pancreatic ductal adenocarcinoma. Three of these proteins were correlated with clinical outcomes in patients, among which SLC41A1 was downregulated in tumour. Overexpression of SLC41A1 suppressed orthotopic tumour growth in a mouse model and reduced the cell proliferation, colony formation, and invasiveness of KP3 and Panc-1 cells, which may have been associated with the increased population of apoptotic-prone cells. Overexpression of SLC41A1 reduced the mitochondrial membrane potential, induced Bax while suppressed Bcl-2 expression. Suppression of Bax abrogated the tumour-suppressive effects of SLC41A1. Furthermore, overexpression of SLC41A1 promoted Mg2+ efflux and suppressed Akt/mTOR activity, which is the upstream regulator of Bax and Bcl-2. An increase in Akt activity and supplementation with Mg2+ abolished SLC41A1-induced tumour suppression. The results of this study suggest that SLC41A1 may be a potential target for the treatment of pancreatic ductal adenocarcinoma.

TAM Infiltration Differences in "Tumor-First" and " ZHENG-First" Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer.

BACKGROUND: Syndrome ( ZHENG in Chinese) in traditional Chinese medicine (TCM) refers to the intrinsic characteristics of a pathological process at a certain stage; these characteristics are influenced by internal and external environments and reveal the nature of a disease. Proper syndrome differentiation is the basic principle that guides clinical treatment. OBJECTIVE: To have a good understanding of tumor progression and the different mechanisms related to ZHENG that have occurred before and after tumor development and to explore the valid evaluation criteria of different pancreatic cancer syndromes to improve the guiding role of TCM syndrome differentiation in pancreatic cancer treatment. METHODS: In this study, we established mouse subcutaneous pancreatic cancer models, namely, Con (control), Pi-Xu (Spleen-Deficiency), Shi-Re (Dampness-Heat), and Xue-Yu (Blood-Stasis). Then, for the first time, we compared the different effects of " ZHENG-first" (referring to a different disease status that occurred before tumor occurrence) and "Tumor-first" (referring to the change in the tumor microenvironment and the resulting changes in the state of the body) conditions on tumor progression and evaluated the associated molecular mechanisms. RESULTS: We found that tumor growth in the " ZHENG-first" and "Tumor-first" conditions was different. In the "Tumor-first" model, the tumor growth in the Pi-Xu group was faster than that in the other groups. However, in the " ZHENG-first" model, the tumor growth trend was most obvious in the Shi-Re group. There was a difference in tumor-associated macrophage infiltration between the 2 models. The expression levels of the inflammatory cytokines IL-6, IL-10, and P-STAT3 were also differentially altered. CONCLUSION: The emergence of ZHENG conditions before or after tumor occurrence had different impacts on pancreatic cancer development, and these impacts may be related to differences in tumor-associated macrophage infiltration and the involved inflammatory cytokines IL-6, IL-10, and P-STAT3. The study results uncovered the molecular basis of syndrome differentiation in pancreatic cancer progression, which might provide more specific guidance for TCM treatment of pancreatic cancer.

Effect of transcutaneous electrical acupoint stimulation combined with palonosetron on chemotherapy-induced nausea and vomiting: a single-blind, randomized, controlled trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting adversely affects the quality of life of patients who receive chemotherapy via intravenous infusion or transcatheter arterial chemoembolization (TACE). This study aimed to investigate the clinical effects of transcutaneous electrical acupoint stimulation (TEAS) on nausea and vomiting after TACE. METHODS: A total of 142 patients who received TACE with cisplatin for primary or metastatic liver cancer were assigned to the active-acupuncture (n = 72) or placebo-acupuncture (n = 70) groups using a covariate-adaptive randomization at a ratio of 1:1. The acupoints Hegu (LI4), Neiguan (P6), and Zusanli (ST36) were stimulated twice daily for 6 days. The effects of TEAS on nausea and vomiting were assessed by using occurrence rate and severity of these symptoms. Anorexia scale and M. D. Anderson Symptom Inventory (MDASI) scores were secondary endpoints and were used to assess the effect of TEAS on patient appetite and quality of life. The safety of the treatments was also monitored. RESULTS: Between the two groups, the differences in occurrence rates and severities of nausea and vomiting after TACE were not significant (all P > 0.05). From the second day after TACE, anorexia scores were significantly lower in the active-acupuncture group than in the placebo-acupuncture group and continued to decrease over time with treatment (all P values less than 0.01). On days 0, 1, and 2, the mean MDASI scores for the active-acupuncture group were slightly lower than those for the placebo-acupuncture group, but the differences were not statistically significant (all P > 0.05). No significant differences were found between the two groups in the occurrence rate of any adverse event (P > 0.05). CONCLUSION: TEAS appears to be a safe and effective therapy to relieve patients' gastrointestinal discomfort after chemotherapy. Trial registration NCT01895010. Registered 21 June 2013.

High expression of erythropoietin-producing hepatoma cell line-B2 (EphB2) predicts the efficiency of the Qingyihuaji formula treatment in pancreatic cancer CFPAC-1 cells through the EphrinB1-EphB2 pathway.

Our previous study demonstrated that inhibition of erythropoietin-producing hepatoma cell line-B2 (EphB2) expression resulted in the promotion of cancer growth, with EphB2 acting as a tumor suppressor in pancreatic cancer. Qingyihuaji formula (QYHJ), a traditional Chinese medicine, acts as an independent protective factor for pancreatic cancer patient survival and different patients have shown various responses to QYHJ treatment. In the current study, the different effects on tumor growth inhibition following QYHJ treatment in cells with different levels of EphB2 expression were investigated to reveal the mechanism. A subcutaneously transplanted tumor model using cancer cells with different levels of EphB2 expression were established in vivo and received a four-week QYHJ intervention. Tumor weight inhibitory rate and tumor volume deflation were evaluated. The cell cycle and apoptosis were analyzed by flow cytometry, and reverse transcription polymerase chain reaction and western blot analysis were used to assess mRNA and protein levels. The results showed that the tumor weight inhibitory rate was 31.40, 31.33 and 18.36% in CFPAC-1, CFPAC-1 control RNAi and CFPAC-1 EphB2 RNAi cells following QYHJ treatment, respectively. A statistically significant difference was identified in CFPAC-1 (P<0.05) and CFPAC-1 control RNAi (P<0.01) cells. In addition, a statistically significant increase was identified in the G0/G1 phase population (P<0.05) and a statistically significant decrease was identified in the S phase population (P<0.05) in CFPAC-1 and CFPAC-1 control RNAi cells; however, no significant difference was identified in the CFPAC-1 EphB2 RNAi cells following QYHJ treatment. QYHJ upregulated the mRNA and protein level of Eph receptor-interacting B1 (EphrinB1) in the cells that were expressing different levels of EphB2, however, QYHJ did not regulate EphB2 expression. In CFPAC-1 and CFPAC-1 control RNAi cells, the QYHJ treatment resulted in a statistically significant decrease in cyclin-dependent kinase 6 (CDK6) mRNA (P<0.05) and protein (P<0.05) levels. The high expression of EphB2 predicted the superior response rate to the QYHJ treatment through a mechanism of inhibiting the cell cycle by an EphrinB1-EphB2-induced CDK6 decrease in CFPAC-1 cells. Therefore, EphB2 acts as a predictive factor for QYHJ treatment in pancreatic cancer CFPAC-1 cells.

[Exploration on the function and clinical significance of meridians and collaterals in tumor metastasis based on Quepen (ST 12)].

The relationship among Quepen (ST 12), meridians that run through Quepen(ST 12) and primary lesion of tumor that metastasized to supraclavicular lymph node [the location of Quepen (ST 12)] are analyzed on the basis of the meridians-collaterals theory, investigation on literature and clinical practice and the clinical feature that varies primary tumor are always bound to supraclavicular lymph node metastasis. Integrated with clinical practice, the function and clinical significance of meridians and collaterals in treating cancer are preliminarily put for ward. The tumor and it's metastasis that locate in the regions where the meridians run through are taken into consideration in acknowledging and treating disease.

[Clinical observation of transarterial chemoembolization combined with sorafenib for advanced hepatocellular carcinoma].

OBJECTIVE: To observe the efficacy and side effects of transarterial chemoembolization (TACE) combined with sorafenib for advanced hepatocellular carcinoma (HCC). METHODS: Forty patients with HCC were treated with sorafenib (400 mg bid) after TACE. The efficacy was evaluated according to RECIST 1.1 criteria, and side effects were assessed by NCI CTC 3.0 criteria. RESULTS: Among the forty cases, one case achieved complete remission (CR), seven cases achieved partial remission (PR), nineteen cases achieved stable disease (SD) and thirteen cases had progressive disease (PD). The disease control rate (DCR) was 67.5%. The overall survival time was 1 - 18 months, and 1-year survival rate was 54.0%. The major adverse events were hand-foot skin reaction, diarrhea and thrombocytopenia. CONCLUSION: The combined therapy of TACE and sorafenib is effective and well tolerated for advanced HCC.

The molecular mechanisms of traditional Chinese medicine ZHENG syndromes on pancreatic tumor growth.

BACKGROUND: Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. OBJECTIVE: To evaluate the specific effect of TCM ZHENG on tumor growth and to examine the molecular mechanisms underlying ZHENG and tumor growth. METHODS: The authors established subcutaneous tumor models of pancreatic cancer ZHENG syndromes of Damp heat (Shi-Re) and Spleen deficiency (Pi-Xu). Tissue samples of the subcutaneous transplanted tumors from each model were studied versus control tumors. CCR5 and CXCR4 proteins in these tissues were assayed by immunohistochemical staining. The expression of CCR5/CCL5/CCL4/CCL3 and CXCR4/SDF-1 mRNA was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). SDF-1, CCL4, CCL5, and CCL3, which are ligands of CXCR4 and CCR5, were examined by ELISA. RESULTS: The study found that tumor models with different ZHENG were successfully established in each group; the tumor growth of Shi-Re group was slower than that of the control group. It was found that there was a significant difference in CCR5 mRNA expression levels among the Pi-Xu, Shi-Re, and control groups. The results of immunohistochemistry staining revealed that the positive rate of CCR5 protein in Shi-Re group, Pi-Xu group, and control group was 25.00%, 53.33%, 83.33%, respectively. The Shi-Re group expressed the lowest levels of CCL5 and CCL4. CONCLUSION: The results of the study suggest that the existence of TCM ZHENG may influence the tumor growth in pancreatic cancer, which might be mediated by the expression of CCR5/CCL5/CCL4. This finding may lead to the development of TCM ZHENG as a prognostic indicator in pancreatic tumor growth.

Ski acts as therapeutic target of qingyihuaji formula in the treatment of SW1990 pancreatic cancer.

BACKGROUND: Qingyihuaji formula (QYHJ) is a widely used herbal formula that has shown promising antitumor effect in the treatment of pancreatic cancer in the Cancer Hospital, Fudan University, Shanghai, China. OBJECTIVE: This research was conducted to study whether Ski acts as a therapeutic target of QYHJ formula in the treatment of SW1990 pancreatic cancer. METHODS: The expression changes of Ski mRNA and protein in SW1990 pancreatic cancer subcutaneously transplanted tumor treated with QYHJ were detected by real-time polymerase chain reaction and Western blot. Then, we established a stable transfection SW1990 cell with low expression of Ski through lentivirus-mediated RNA interference (RNAi) technique. The responses to QYHJ treatment on a subcutaneously transplanted tumor with different Ski expression statuses were evaluated. Finally, the effect of Ski downregulation on SW1990 cell biological behavior was also evaluated. RESULTS: Expression of Ski mRNA and protein in SW1990 subcutaneously transplanted tumor decreased dramatically after the treatment with QYHJ. Stable transfection cells with low expression of Ski (SW1990/Ski RNAi) were created, and negative vector-transfected cells (SW1990/con RNAi) were used as controls. The tumor weight inhibitory rates of QYHJ on subcutaneously transplanted tumors formed by SW1990 or SW1990/con RNAi were 29.6% and 32.2%, respectively, whereas they were 16.0% to 17.8% when the tumors were formed by SW1990/Ski RNAi. Ski downregulation sensitized the response of SW1990 cells to TGF-beta1-induced growth inhibition in vitro. Flow cytometric analyses revealed that the percentage of cells in the G1 phase increased from 40.4% to 62.9% when Ski was downregulated. The subcutaneously transplanted tumors formed by SW1990/Ski RNAi grew much more slowly than those formed by parental and control vector-transfected cells. CONCLUSION: Ski acts as therapeutic target of QYHJ in the treatment of SW1990 pancreatic cancer cells, and its expression status mediates different responses to QYHJ treatment.

Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial.

AIM: To examine whether acupuncture can prevent prolonged postoperative ileus (PPOI) after intraperitoneal surgery for colon cancer. METHODS: Ninety patients were recruited from the Fudan University Cancer Hospital, Shanghai, China. After surgery, patients were randomized to receive acupuncture (once daily, starting on postoperative day 1, for up to six consecutive days) or usual care. PPOI was defined as an inability to pass flatus or have a bowel movement by 96 h after surgery. The main outcomes were time to first flatus, time to first bowel movement, and electrogastroenterography. Secondary outcomes were quality of life (QOL) measures, including pain, nausea, insomnia, abdominal distension/fullness, and sense of well-being. RESULTS: No significant differences in PPOI on day 4 (P = 0.71) or QOL measures were found between the groups. There were also no group differences when the data were analyzed by examining those whose PPOI had resolved by day 5 (P = 0.69) or day 6 (P = 0.88). No adverse events related to acupuncture were reported. CONCLUSION: Acupuncture did not prevent PPOI and was not useful for treating PPOI once it had developed in this population.

[Clinical observation on electric stimulation of Yongquan (KI 1) for prevention of nausea and vomiting induced by Cisplatin].

OBJECTIVE: To search for an effective method for controlling nausea and vomiting induced by chemotherapy. METHODS: Eighty-eight cases of hepatic cancer with interventional therapy of Cisplatin were randomly divided into a treatment group and a control group, 44 cases in each group. The treatment group were treated with an antiemetic and electroacupuncture at Yongquan (KI 1), and the control group only with the antiementic. The controlling rates for nausea and vomiting were compared between the two groups. RESULTS: The controlling rates for acute nausea, vomiting and delayed vomiting in the treatment group were better than those in the control group (P < 0.05). CONCLUSION: Electroacupuncture at Yongquan (KI 1) can better prevent and improve the symptoms of nausea and vomiting in the patient with chemotherapy of Cisplatin.

[Clinical evaluation of integration of transcatheter arterial chemoembolization and traditional Chinese medicine in treating metastatic liver cancer].

OBJECTIVE: To evaluate the treatment effect, quality of life and side-effect of transcatheter arterial chemoembolization (TACE) and traditional Chinese medicine (TCM) in treating metastatic liver cancer. METHODS: Thirty-nine cases of colon metastatic liver cancer were randomly divided into two groups. Both TACE and TCM were used in the treatment group, while only TACE was used in the control group. The drug used in TACE included floxuridine, pirarubicin, cisplatin, and the herbs for strengthening the spleen and regulating Qi were used in TCM. RESULTS: The response rate in the treatment group was 30% (45% including minor remission patients), and the median survival time was 18.6 months. While in the control group the response rate was 15.8% (36.8% including minor remission patients), and the median survival time was 14.3 months. The 1-, 2-, 3- year survival rates of treatment group and the control group were 70.2%, 40.3%, 13.0% and 68.7%, 29.5%, 10.3% respectively. There were fewer other organ metastases in the treatment group. The score from the EORTC quality of life questionnaire QLQ-C30 in treatment group was higher than that in the control group. CONCLUSION: Integration of TACE and TCM in treating colon metastatic liver cancer has better results.