Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy.

BACKGROUND & AIMS: Either activation of mTORC1 due to loss of Tsc1 (tuberous sclerosis complex 1) or defective hepatic autophagy due to loss of Atg5 leads to spontaneous liver tumorigenesis in mice. The purpose of this study was to investigate the mechanisms by which autophagy contributes to the hepatic metabolic changes and tumorigenesis mediated by mTORC1 activation. METHODS: Atg5 Flox/Flox (Atg5F/F) and Tsc1F/F mice were crossed with albumin-Cre mice to generate liver-specific Atg5 knockout (L-Atg5 KO), L-Tsc1 KO and L-Atg5/Tsc1 double KO (DKO) mice. These mice were crossed with p62/Sqstm1F/F (p62) and whole body Nrf2 KO mice to generate L-Atg5/Tsc1/p62 and L-Atg5/Tsc1-Nrf2 triple KO mice. These mice were housed for various periods up to 12 months, and blood and liver tissues were harvested for biochemical and histological analysis RESULTS: Deletion of Atg5 in L-Tsc1 KO mice inhibited liver tumorigenesis but increased mortality and was accompanied by drastically enhanced hepatic ductular reaction (DR), hepatocyte degeneration and metabolic reprogramming. Deletion of p62 reversed DR, hepatocyte degeneration and metabolic reprogramming as well as the mortality of L-Atg5/Tsc1 DKO mice, but unexpectedly promoted liver tumorigenesis via activation of a group of oncogenic signaling pathways. Nrf2 ablation markedly improved DR with increased hepatocyte population and improved metabolic reprogramming and survival of the L-Atg5/Tsc1 DKO mice without tumor formation. Decreased p62 and increased mTOR activity were also observed in a subset of human hepatocellular carcinomas. CONCLUSIONS: These results reveal previously undescribed functions of hepatic p62 in suppressing tumorigenesis and regulating liver cell repopulation and metabolic reprogramming resulting from persistent mTORC1 activation and defective autophagy. LAY SUMMARY: Metabolic liver disease and viral hepatitis are common chronic liver diseases and risk factors of hepatocellular carcinoma, which are often associated with impaired hepatic autophagy and increased mTOR activation. Using multiple genetically engineered mouse models of defective hepatic autophagy and persistent mTOR activation, we dissected the complex mechanisms behind this observation. Our results uncovered an unexpected novel tumor suppressor function of p62/Sqstm1, which regulated liver cell repopulation, ductular reaction and metabolic reprogramming in liver tumorigenesis.

NOV/CCN3 Promotes Cell Migration and Invasion in Intrahepatic Cholangiocarcinoma via miR-92a-3p.

Intrahepatic cholangiocarcinoma (ICC) is a common type of human cancer with a poor prognosis, and investigating the potential molecular mechanisms that can contribute to gene diagnosis and therapy. Herein, based on the recently concerned vertebrate-specific Cyr61/CTGF/NOV (CCN) gene family because of its important roles in diverse diseases, we obtained NOV/CCN3 to query for its potential roles in tumorigenesis via bioinformatics analysis. Experimental validations confirmed that both NOV mRNA and protein are up-regulated in two ICC cell lines, suggesting that it may promote cell migration and invasion by promoting EMT. To elucidate the detailed regulatory mechanism, miR-92a-3p is screened and identified as a negative regulatory small RNA targeting NOV, and further experimental validation demonstrates that miR-92a-3p contributes to NOV-mediated migration and invasion of ICC via the Notch signaling pathway. Our study reveals that NOV may be a potential target for diagnosing and treating ICC, which will provide experimental data and molecular theoretical foundation for cancer treatment, particularly for future precision medicine.

FOXM1 inhibitor, Siomycin A, synergizes and restores 5-FU cytotoxicity in human cholangiocarcinoma cell lines via targeting thymidylate synthase.

AIMS: 5-Fluorouracil (5-FU), a thymidylate synthase (TS) inhibitor, has been used as the first-line chemotherapeutic drug for cholangiocarcinoma (CCA). The side effects and drug resistance have developed the limits of the clinical application of 5-FU in CCA treatment. Upregulation of Forkhead box M1 (FOXM1) and TS were shown to play a significant role in 5-FU resistance. In this study, the effect of Siomycin A (SioA), a FOXM1 inhibitor, on enhancing 5-FU cytotoxicity and reversing 5-FU resistance in CCA cell lines were demonstrated. MAIN METHODS: Human CCA cell lines, KKU-100 and KKU-213A were used. Cell viability was determined using MTT assay. Expression of FOXM1 and TS proteins were determined using Western blotting. FOXM1 mRNA expression was quantitated using real-time PCR. The combination and dose reduction (DRI) were analyzed according to the Chou and Talalay method. KEY FINDING: Single drug treatment of 5-FU and SioA effectively inhibited CCA cell growth in dose and time dependent fashions. The two CCA cell lines had different responses to 5-FU but exhibited similar sensitivity to SioA. FOXM1 and TS expression were increased in the 5-FU treated cells but were suppressed in the SioA treated cells. A direct binding of SioA, to TS and 5,10-methylene-tetrahydrofolate as an inactive ternary complex was simulated. The combined treatment of 5-FU with SioA showed a synergistic effect with a high DRI and restored 5-FU sensitivity in the 5-FU resistant cells. SIGNIFICANCE: Targeting FOXM1 using SioA in combination with 5-FU might be a strategy to overcome the 5-FU resistance in CCA.

FGFR Inhibitors: Clinical Activity and Development in the Treatment of Cholangiocarcinoma.

PURPOSE OF REVIEW: Cholangiocarcinoma is an aggressive cancer with a poor prognosis and limited treatment. Gene sequencing studies have identified genetic alterations in fibroblast growth factor receptor (FGFR) in a significant proportion of cholangiocarcinoma (CCA) patients. This review will discuss the FGFR signaling pathway's role in CCA and highlight the development of therapeutic strategies targeting this pathway. RECENT FINDINGS: The development of highly potent and selective FGFR inhibitors has led to the approval of pemigatinib for FGFR2 fusion or rearranged CCA. Other selective FGFR inhibitors are currently under clinical investigation and show promising activity. Despite encouraging results, the emergence of resistance is inevitable. Studies using circulating tumor DNA and on-treatment tissue biopsies have elucidated underlying mechanisms of intrinsic and acquired resistance. There is a critical need to not only develop more effective compounds, but also innovative sequencing strategies and combinations to overcome resistance to selective FGFR inhibition. Therapeutic development of precision medicine for FGFR-altered CCA is a dynamic process of involving a comprehensive understanding of tumor biology, rational clinical trial design, and therapeutic optimization. Alterations in FGFR represent a valid therapeutic target in CCA and selective FGFR inhibitors are treatment options for this patient population.

Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway.

Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.

Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: a case report.

OBJECTIVE: Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy after hepatocellular carcinoma. The current standard palliative treatment, chemotherapy regimen with gemcitabine and cisplatin, prolongs overall survival only of a few months. Established locoregional therapies are not a curative option or an alternative to surgery in the treatment of CCA. We report a case of a patient affected by a cholangiocellular carcinoma at hepatic hilum treated by Electrochemotherapy (ECT) at our oncologic center. CASE PRESENTATION: A 71 years old male affected by a CCA at hepatic hilum was treated with ECT according to ESOPE guidelines. No complications occurred during ECT procedure. The patient was discharged after 10 days. The functional MR evaluation at 2 and at 4 months post-treatment showed a significant response without significant post-treatment adverse events. The Computed tomography (CT) assessment after 18 months did not show progression of disease. CONCLUSIONS: ECT is safe and its use could be suggested as a palliative treatment of advanced neoplastic lesions in which radical surgical treatment is not possible.

NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121).

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m2)/cisplatin (25 mg/m2) or gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. (Investigational new drug (IND) number: 139058, European Clinical Trials database: EudraCT Number 2019-001025-28, ClinicalTrials.gov identifier: NCT04163900).

Alterations in DNA Damage Repair Genes in Primary Liver Cancer.

PURPOSE: Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC). EXPERIMENTAL DESIGN: Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board. RESULTS: A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response. CONCLUSIONS: The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.

MET­RON dual inhibitor, BMS­777607, suppresses cholangiocarcinoma cell growth, and MET­RON upregulation indicates worse prognosis for intra­hepatic cholangiocarcinoma patients.

Intra­hepatic cholangiocarcinoma (CCA) is an aggressive cancer with few effective therapeutic options. MET and RON have been found to be increased in a variety of tumors and to be associated with tumor progression and acquired resistance to therapy. The present study evaluated the efficacy of a MET­RON dual inhibitor (BMS­777607) for treating CCA and analyzed the prognostic significance of MET­RON upregulation. We treated CCA cell lines and rats with CCA with BMS­777607 to determine its effects on tumor growth and measured the MET­RON protein expression in samples obtained from 96 patients with CCA who previously underwent hepatectomies. A clonogenic assay revealed that BMS­777607 inhibited the growth of HuCCT1 and KKU­100 human CCA cells. It also decreased tumor growth in CCA rats. MET­RON upregulation independently predicted poor survival for CCA patients who previously underwent hepatectomies. In conclusion, MET­RON upregulation is a poor prognostic factor in CCA patients receiving hepatectomies and may be targeted using BMS­77760.

9-cis-retinoic acid elevates MRP3 expression by inhibiting sumoylation of RXRα to alleviate cholestatic liver injury.

AIMS: Vitamin A and its metabolites has been found to be protective against cholestatic liver injury, but the exact underlying mechanisms involved in cholestatic liver injury remain unclear. The objective of this study was to determine the function and mechanisms of 9-cis-retinoic acid, the metabolite of vitamin A, in cholestatic liver injury. METHODS: The bile duct ligated (BDL) mice were treated with 9-cis-retinoic acid by intravenous injection through the tail for 10 days. The liver function and histology were assessed in the matched group and experimental group. The expression of MRP3 in liver tissue was tested by qRT-PCR, Western blotting, and IHC. Effect of RXRα sumoylation on MRP3 expression was investigated at a cellular level. Influence of 9-cis-retinoic acid on RXRα sumoylation was also tested in cells. RESULTS: Our findings showed that 9-cis-retinoic acid significantly decreases the serum ALT and AST level, alleviates hepatic necrosis of the BDL-mice. We also identified MRP3, an important protective hepatobiliary transporter in cholestasis, was elevated by 9-cis-retinoic acid in vivo and in vitro. 9-cis-retinoic acid weakened the sumoylation of RXRα, which promotes the cytoplasmic location of RXRα and lightens the interaction of RXRα and RARα. Inhibition of RXRα and RARα interaction increased MRP3 expression. CONCLUSIONS: 9-cis-retinoic acid alleviates cholestatic liver injury by elevating MRP3 expression through its mechanism of inhibiting sumoylation of RXRα.

Multicenter retrospective analysis of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log-rank test determined the significance of each prognostic factor. Elevated alpha-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First-line chemotherapy included platinum-containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression-free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child-Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum-containing regimens (HR: 15.83 [95% CI: 2.25-111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second-line therapy. In conclusion, the platinum-containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

The clinical significance and biological function of interferon regulatory factor 1 in cholangiocarcinoma.

Interferon regulatory factor 1 (IRF1) has been suggested to act as a tumor suppressor in human cancers. However, the clinical significance and biological function of IRF1 in cholangiocarcinoma is poorly understood. In our results, IRF1 mRNA and protein expressions were decreased in cholangiocarcinoma tissues and cell lines compared with paired normal hepatic tissues and intrahepatic bile duct epithelial cell line. IRF1 protein low-expression was associated with tumor stage, tumor size, vascular invasion and metastasis and served as a poor independent prognostic parameter in cholangiocarcinoma patients. Up-regulation of IRF1 expression suppressed cholangiocarcinoma cells proliferation, migration and invasion, and blocked cell cycle progression, but has no effect on apoptosis. In conclusion, IRF1 is low-expressed in cholangiocarcinoma tissues and cell lines, and correlated with malignant status and prognosis in cholangiocarcinoma patients. IRF1 served as tumor suppressor in the regulation of cholangiocarcinoma cells proliferation, cell cycle, migration and invasion.

Prognostic Factors for Survival in Patients with Advanced Intrahepatic Cholangiocarcinoma Treated with Gemcitabine plus Cisplatin as First-Line Treatment.

OBJECTIVES: Intrahepatic cholangiocarcinoma (ICC) is a rare type of liver cancer. No clinically useful prognostic factors have been reported for patients with advanced ICC. In the present study, we aimed to evaluate the clinical prognostic factors of patients with advanced ICC receiving gemcitabine plus cisplatin combination therapy (GC) as standard first-line chemotherapy. METHODS: A retrospective analysis was performed of the data of patients with ICC treated at our institution from March 2011 to January 2016. We used the Cox regression model and estimated the hazard ratios of potential prognostic factors for survival. RESULTS: Of 216 patients with biliary tract cancer receiving GC as first-line chemotherapy, we extracted data for 77 patients who were diagnosed with ICC and received GC as first-line chemotherapy. The median overall survival was 13.8 months (95% CI, 8.9-18.6). In multivariate analysis, pretreatment serum lactate dehydrogenase (hazard ratio [HR]: 2.53, p = 0.005), C-reactive protein (HR: 3.06, p = 0.001), and carcinoembryonic antigen (HR: 2.39, p = 0.03) levels were significantly associated with overall survival. CONCLUSIONS: Readily available clinical laboratory values reliably predicted the prognosis of ICC patients receiving GC therapy. If validated in other studies, these results may provide a useful tool for individual patient-risk evaluation and the design and interpretation of future trials.

Acute vanishing bile duct syndrome after therapy with cephalosporin, metronidazole, and clotrimazole: A case report.

RATIONALE: Vanishing bile duct syndrome (VBDS) consists of a series of diseases characterized by the loss of >50% bile duct in portal areas. Many factors are associated with VBDS including infections, neoplasms, and drugs. Antibiotic is one of the most frequently reported causes of VBDS. PATIENT CONCERNS: A 29-year-old female was admitted because of liver injury for over 3 months. Tests for viruses that can cause hepatitis and autoantibodies were all negative. She was prescribed with antibiotics approximately a week before liver injury while there was no history of alcohol consumption. DIAGNOSES: Liver biopsy demonstrated a loss of intrahepatic bile duct in most of the portal tracts. INTERVENTIONS: This patient was treated with ursodeoxycholic acid, polyene phosphatidylcholine, and bicyclol. Most importantly, the treatments in our hospital were proved by the ethics committee of Department of Infectious Disease, Anhui Provincial Hospital. OUTCOMES: The symptoms were improved. She is still under treatment. LESSONS: VBDS is rare but can be severe. A liver biopsy offers an important evidence for the diagnosis of VBDS, especially for those with a history of susceptible drugs taking.

Micro-RNA-130a-3p Regulates Gemcitabine Resistance via PPARG in Cholangiocarcinoma.

BACKGROUND: The prognosis of cholangiocarcinoma (CCA) is so poor that its chemoresistance needs to be reduced. In this study, we focused on the microRNAs (miRNAs) associated with gemcitabine resistance of CCA and assessed the clinical significance of miRNAs and their target genes. METHODS: We performed miRNA microarray analysis for two CCA cell lines (CCLP-1 and MzChA-1) and their gemcitabine-resistant (GR) cells. An miR-130a-3p mimic was induced into CCA cells using lipofection, and we used pioglitazone as a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in vitro. The expression of miR-130a-3p was studied in 27 intrahepatic CCA samples after laser capture microdissection (LCM) and by immunohistochemistry from patients who had undergone curative resection from March 2004 to November 2012 at Osaka University Hospital. RESULTS: miR-130a-3p expression was upregulated in CCLP-1-GRs and MzChA-1-GRs significantly more than in their parental cells. Transfection of the miR-130a-3p mimic into CCA cells increased gemcitabine resistance, and we detected PPARG as a target gene of miR-130a-3p. Furthermore, pioglitazone had a synergistic effect with gemcitabine and alleviated gemcitabine resistance of CCA GR cells. Moreover, clinical examination revealed that for patients who underwent adjuvant gemcitabine therapy, those who were PPARγ positive had significantly longer disease-free survival than those who were PPARγ negative (n = 5 and 11, respectively; p = 0.027). CONCLUSIONS: Our data suggest that miR-130a-3p was associated with gemcitabine resistance in CCA through PPARG, and there is a possibility that pioglitazone can be used for the treatment of CCA.

Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study.

Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of sorafenib combined with best supportive care (BSC) in these patients. We enrolled 44 patients with unresectable and advanced ICC who were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12, and the secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Our results showed that the DCR was 15.9%, the median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). AEs of grades 1 and 2 events occurred in 75% of patients, and AE of grade 4 (severe) was observed in 1 patient. Therefore, sorafenib in combination with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC.

Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a malignant epithelial neoplasm composed of cells resembling cholangiocytes that line the intrahepatic bile ducts in portal areas of the hepatic lobule. Although ICC has been defined as a tumor arising from cholangiocyte transformation, recent evidence from genetic lineage-tracing experiments has indicated that hepatocytes can be a cellular origin of ICC by directly changing their fate to that of biliary lineage cells. Notch signaling has been identified as an essential factor for hepatocyte conversion into biliary lineage cells at the onset of ICC. However, the mechanisms underlying Notch signal activation in hepatocytes remain unclear. Here, using a mouse model of ICC, we found that hepatic macrophages called Kupffer cells transiently congregate around the central veins in the liver and express the Notch ligand Jagged-1 coincident with Notch activation in pericentral hepatocytes. Depletion of Kupffer cells prevents the Notch-mediated cell-fate conversion of hepatocytes to biliary lineage cells, inducing hepatocyte apoptosis and increasing mortality in mice. These findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease.

The anticancer effects of Resina Draconis extract on cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a relatively rare, heterogeneous malignant tumor with poor clinical outcomes. Because of high insensitivity to chemotherapy and radiotherapy, there are no effective treatment options. Efforts to identify and develop new agents for prevention and treatment of this deadly disease are urgent. Here, we assessed the apoptotic cytotoxicity of Resina Draconis extract (RDE) using in vitro and in vivo assays and identified the mechanisms underlying antitumor effects of RDE. RDE was obtained via vacuum distillation of Resina Draconis with 75 % ethanol. The ethanol extract could inhibit CCA cell proliferation and trigger apoptotic cell death in both QBC939 and HCCC9810 cell lines in a time- and concentration-dependent manner. RDE treatment resulted in intracellular caspase-8 and poly (ADP-ribose) polymerase protease activation. RDE significantly downregulated antiapoptotic protein survivin expression and upregulated proapoptotic protein Bak expression. RDE also inhibited CCA tumor growth in vivo. We observed that human CCA tissues had much higher survivin expression than did paired adjacent normal tissue. Taken together, the current data suggested that RDE has anticancer effects on CCA, and that RDE could function as a novel anticancer agent to benefit patients with CCA.