Scoparone induces autophagic cell death via the PAK1/AKT axis in colorectal cancer.

Colorectal cancer (CRC) is one of most common malignancies worldwide, yet curative therapy remains a clinical challenge. Here, we demonstrate that scoparone (Scop), a traditional Chinese medicine monomer, inhibits the growth of CRC cells both in vitro and in vivo. Further studies found that Scop treatment induces complete autophagic flux in CRC cells, while inhibition of autophagy markedly represses the antiproliferative activities of Scop, suggesting an antitumour property of Scop-induced autophagy in CRC. Mechanistically, Scop induced autophagy initiation by reducing P21-activated kinase 1 (PAK1) expression and subsequently repressing the AKT/mTOR signaling pathway. Collectively, our study suggests that Scop is a potential anti-CRC therapeutic option and provides an underlying molecular mechanism for its antitumour effect in CRC.

Discovery of canine drug toceranib phosphate as a repurposed agent against human hepatocellular carcinoma.

BACKGROUND AND AIMS: Human hepatocellular carcinoma (HCC) is an aggressive malignancy with poor clinical outcomes. There are limited therapeutic options for those diagnosed with terminal HCC and therefore incorporating novel agents into standard-of-care regimens is urgently needed. In contrast to de novo drug discovery, the strategy of repurposing compounds initially designed to treat animals might yield substantial advantages in terms of efficacy and safety. Given the evidence for the clinical efficacy of toceranib phosphate (TOC) against canine carcinomas, we aimed to investigate its therapeutic effect on human HCC. METHODS: The antitumor effects of TOC were evaluated using human HCC cell lines and cell-line-derived xenograft models. Changes in autophagic response upon TOC exposure were quantified through immunoblotting and immunofluorescence analysis. The role of TOC-triggered autophagy was addressed via pharmacological and genetic inhibition. RESULTS: We demonstrated TOC exhibited potent antitumor activity against human HCC cells by stimulating apoptosis in vitro and in vivo by a concomitant increase in autophagic flux. Blocking the TOC-triggered autophagy inhibited cellular proliferation and decreased tumour burden, indicating a protective role of autophagy against TOC-mediated HCC cell death. This role played by TOC-induced autophagy was further linked to the inactivation of the Akt/mTOR pathway that could be attributed to the upregulation of Cyr61. Moreover, treatment with sorafenib plus TOC resulted in pronounced synergistic effects on HCC cells. CONCLUSION: Our results elucidate a newly identified therapeutic potential of TOC in treating HCC, sparking a growing interest in repurposing such canine drugs for human use.

CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis.

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.

Repurposing antifungal drugs for cancer therapy.

BACKGROUND: Repurposing antifungal drugs in cancer therapy has attracted unprecedented attention in both preclinical and clinical research due to specific advantages, such as safety, high-cost effectiveness and time savings compared with cancer drug discovery. The surprising and encouraging efficacy of antifungal drugs in cancer therapy, mechanistically, is attributed to the overlapping targets or molecular pathways between fungal and cancer pathogenesis. Advancements in omics, informatics and analytical technology have led to the discovery of increasing "off-site" targets from antifungal drugs involved in cancerogenesis, such as smoothened (D477G) inhibition from itraconazole in basal cell carcinoma. AIM OF REVIEW: This review illustrates several antifungal drugs repurposed for cancer therapy and reveals the underlying mechanism based on their original target and "off-site" target. Furthermore, the challenges and perspectives for the future development and clinical applications of antifungal drugs for cancer therapy are also discussed, providing a refresh understanding of drug repurposing. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review may provide a basic understanding of repurposed antifungal drugs for clinical cancer management, thereby helping antifungal drugs broaden new indications and promote clinical translation.

Prevalence and prognostic impact of hepatopulmonary syndrome in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization: a prospective cohort study.

BACKGROUND: To determine the prevalence and prognostic impact of hepatopulmonary syndrome (HPS) in patients with unresectable hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). METHODS: Fifty-four patients with unresectable HCC undergoing TACE between December 2014 and December 2015 were prospectively screened for HPS and were followed up for a maximum of 2 years or until the end of this prospective study. RESULTS: Nineteen of the 54 (35.2%) patients were considered to have HPS, including one (5.3%) with severe HPS, nine (47.4%) with moderate HPS, and nine (47.4%) with mild HPS. The median overall survival (OS) was 10.1 (95% confidence interval [CI], 3.9-16.3) months for patients with HPS and 15.1 (95% CI, 7.3-22.9) months for patients without HPS, which is not a significant difference ( P  = 0.100). The median progression-free survival was also not significantly different between patients with and without HPS (5.2 [95% CI, 0-12.8] vs. 8.4 [95% CI, 3.6-13.1] months; P  = 0.537). In the multivariable Cox regression analyses, carbon monoxide diffusing capacity (hazard ratio [HR] = 1.033 [95% CI, 1.003-1.064]; P  = 0.028) and Child-Pugh class (HR = 1.815 [95% CI, 1.011-3.260]; P  = 0.046) were identified to be the independent prognostic factors of OS. CONCLUSION: Mild or moderate HPS is common in patients with unresectable HCC undergoing TACE, but it does not seem to have a significant prognostic impact.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Serum Nardilysin as a Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma.

Background: Nardilysin, (N-arginine dibasic convertase, NRDC) has been reported to play an important role in cancer progression, and is associated with tumor proliferation signals and inflammatory signals, such as tumor necrosis factor-a (TNF-a) and heparin-binding epidermal growth factor-like growth factor (HB-EGF), through the activation of disintegrin and metalloproteinase (ADAM) proteases. NRDC has recently been revealed to be involved in the tumorigenesis of various types of cancer, including intrahepatic cholangiocarcinoma, malignant cerebral infarction, esophageal squamous cell carcinoma, and gastric cancer. However, the expression profiles and biological relevance of NRDC in pancreatic ductal adenocarcinoma have rarely been reported. Methods: We analyzed the NRDC expression profile in pancreatic ductal adenocarcinoma by enzyme-linked immunosorbent assay (ELISA) and identified NRDC as a circulating biomarker in the serum of 112 pancreatic ductal adenocarcinoma patients. The diagnostic value of NRDC was analyzed by the area under the curve (AUC) and the receiver operating characteristic (ROC) test. Results: Our results demonstrated that the clinical prognosis significance of NRDC with the clinical characteristics in pancreatic ductal adenocarcinoma (PDAC). NRDC was notably decreased in PDAC patient serum compared with the control group (p < 0.001). Furthermore, the present study found that the NRDC expression level was correlated with T grade (p < 0.001), metastasis(p < 0.001), differentiation(p < 0.001), and TNM stage (p = 0.011). Further bioinformatics analysis revealed that NRDC correlated with proliferation and migration pathways; in particular, it mediated cell-matrix adhesion-dependent activation in pancreatic ductal adenocarcinoma. Conclusions: Serum NRDC may play a useful diagnostic biomarker to evaluate the aggressive clinical features in PAAD patients.

Identification of Novel Molecular Therapeutic Targets and Their Potential Prognostic Biomarkers Among Kinesin Superfamily of Proteins in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Kinesin superfamily of proteins (KIFs) has been broadly reported to play an indispensable role in the biological process. Recently, emerging evidence reveals its oncogenic role in various cancers. However, the prognostic, oncological, and immunological values of KIFs have not been comprehensively explored in pancreatic ductal adenocarcinoma (PDAC) patients. We aimed to illustrate the relationship between KIFs and pancreatic ductal adenocarcinoma by using bioinformatical analysis. METHODS: We use GEPIA, Oncomine datasets, cBioPortal, LOGpc, TIMER, and STRING bioinformatics tools and web servers to investigate the aberrant expression, prognostic values, and oncogenic role of KIFs. The two-gene prognostic model and the correlation between KIFs and KRAS and TP53 mutation were performed using an R-based computational framework. RESULTS: Our results demonstrated that KIFC1/2C/4A/11/14/15/18A/18B/20B/23 (we name it prognosis-related KIFs) were upregulated and associated with unfavorable clinical outcome in pancreatic cancer patients. KIF21B overexpression is associated with better clinical outcome. The KIFC1/2C/4A/11/14/15/18A/18B/20B/23 profiles were significantly increased compared to grade 1 and grade 2/3. Besides, KIFC1/2C/4A/11/14/15/18A/18B/20B/23 was significantly associated with the mutation status of KRAS and TP53.Notably, most prognosis-related KIFs have strong correlations with tumor growth and myeloid-derived suppressor cells infiltration (MDSCs). A prognostic signature based on KIF20B and KIF21B showed a reliable predictive performance. Receiver operating characteristic (ROC) curve was employed to assess the predictive power of two-gene signature. Consequently, the gene set enrichment analysis (GSEA) showed that KIF20B and KIF21B's overexpression was associated with the immunological and oncogenic pathway activation in pancreatic cancer. Finally, real-time quantitative PCR (RT-qPCR) was utilized to investigate the expression pattern of KIF20B and KIF21B in pancreatic cancer cell lines and normal pancreatic cell. CONCLUSIONS: Knowledge of the expression level of the KIFs may provide novel therapeutic molecular targets and potential prognostic biomarkers to pancreatic cancer patients.

Identification of biomarkers related to Tumor-Infiltrating Lymphocytes (TILs) infiltration with gene co-expression network in colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC.

Repurposing antitussive benproperine phosphate against pancreatic cancer depends on autophagy arrest.

Pancreatic cancer (PC) is one of the most common human malignancies worldwide and remains a major clinical challenge. Here, we found that benproperine phosphate (BPP), a cough suppressant, showed a significant anticancer effect on PC both in vitro and in vivo via the induction of autophagy-mediated cell death. Mechanistic studies revealed that BPP triggered AMPK/mTOR-mediated autophagy initiation and disturbed Ras-related protein Rab-11A (RAB11A)-mediated autophagosome-lysosome fusion, resulting in excessive accumulation of autophagosomes. Inhibition of autophagy or overexpression of RAB11A partially reversed BPP-induced growth inhibition in PC cells, suggesting that BPP might induce lethal autophagy arrest in PC cells. In conclusion, our results identify BPP as a potent antitumor agent for PC via the induction of autophagy arrest, therefore providing a new potential therapeutic strategy for the treatment of PC.

ABO blood type, smoking status, other risk factors and prognosis of pancreatic ductal adenocarcinoma.

The aim of this observational study was to test whether ABO blood type was a prognostic factor for pancreatic ductal adenocarcinoma (PDAC) patients and whether other risk factors could influence pancreatic cancer patients' survival. This study included 610 patients who were diagnosed as pancreatic cancer and had undergone radical surgery. Patients' characteristics included age, gender, tumor stage, tumor grade, adenosquamous carcinoma (ASC) status, preoperative serum carbohydrate antigen 19-9 (CA19-9) levels, preoperative serum carcinoembryonic antigen (CEA) levels, ABO blood type, smoking status, and drinking status were analyzed in this study. Cox proportional hazards regression model and Kaplan-Meier method were used to evaluate the role of prognostic factors. For pancreatic cancer patients undergoing radical surgery, the overall survival was worse for ASC patients than PDAC patients (Log-rank = 11.315, P < .001). Compared with ASC patients (Log-rank < 0.001, P = .996), PDAC patients can benefit from chemotherapy (Log-rank = 17.665, P < .001). For PDAC patients, O blood type had better overall survival than non-O blood type (Log-rank = 4.153, P = .042). Moreover, the group with higher serum levels of CA19-9 had poor prognosis compared to another group with low serum CA19-9 (Log-rank = 4.122, P = .042). Higher CEA levels indicated poor prognosis (Log-rank = 13.618, P < .001). In conclusion, ASC status was associated with overall survival of pancreatic cancer patients and cannot benefit from postoperative chemotherapy. Non-O blood type was a prognostic factor for PDAC patients.

Evaluation of the target genes of arsenic trioxide in pancreatic cancer by bioinformatics analysis.

The aim of the present study was to evaluate the potential network of arsenic trioxide (ATO) target genes in pancreatic cancer. The DrugBank, STITCH, cBioPortal, Kaplan-Meier plotter and Oncomine websites were used to analyze the association of ATO and its target genes with pancreatic cancer. Initially, 19 ATO target genes were identified, along with their associated protein-protein interaction networks and Kyoto Encyclopedia of Genes and Genomes pathways. ATO was found to be associated with multiple types of cancer, and the most common solid cancer was pancreatic cancer. A total of 6 ATO target genes (namely AKT1, CCND1, CDKN2A, IKBKB, MAPK1 and MAPK3) were found to be associated with pancreatic cancer. Next, the mutation information of the 6 ATO target genes in pancreatic cancer was collected. A total of 20 ATO interacting genes were identified, which were mainly involved in hepatitis B, prostate cancer, pathways in cancer, glioma and chronic myeloid leukemia. Finally, the genes CCND1 and MAPK1 were detected to be prognostic factors in patients with pancreatic cancer. In conclusion, bioinformatics analysis may help elucidate the molecular mechanisms underlying the involvement of ATO in pancreatic cancer, enabling more effective treatment of this disease.

Effect of Transjugular Intrahepatic Portosystemic Shunt Creation on Pulmonary Gas Exchange in Patients with Hepatopulmonary Syndrome: A Prospective Study.

PURPOSE: To evaluate effect of transjugular intrahepatic portosystemic shunt (TIPS) creation on pulmonary gas exchange in patients with hepatopulmonary syndrome (HPS). MATERIALS AND METHODS: All patients with cirrhosis or Budd-Chiari syndrome undergoing elective TIPS creation at a single institution between June 2014 and June 2015 were eligible for inclusion. Twenty-three patients with HPS (age 55.0 y ± 14.4; 11 men; Model for End-Stage Liver Disease score 10.2 ± 2.7) who achieved technical success were included in the analysis. Diagnosis of HPS was established by contrast-enhanced echocardiography demonstrating intrapulmonary vascular dilatation and arterial blood gas analysis demonstrating arterial oxygenation defects. RESULTS: Mean portosystemic gradient was reduced from 21.7 mm Hg ± 8.3 before TIPS creation to 10.8 mm Hg ± 5.1 after TIPS creation. Among the 5 (21.7%) patients who experienced dyspnea, 4 (80.0%) reported improvement after TIPS creation. This improvement was not maintained at 3 months after TIPS creation in 2 (50.0%) patients. Compared with before TIPS creation, mean change in alveolar-arterial oxygen gradient for patients with HPS was statistically significant at 1 month (-9.2 mm Hg ± 8.0; P < .001) after TIPS creation, but not at 2-3 days (-0.9 mm Hg ± 10.5; P = .678) or 3 months (-3.4 mm Hg ± 11.8; P = .179) after TIPS creation. CONCLUSIONS: TIPS creation can transiently improve pulmonary gas exchange in patients with HPS.