Berberine chloride suppresses pancreatic adenocarcinoma proliferation and growth by targeting inflammation-related genes: an in silico analysis with in vitro and vivo validation.

PURPOSE: Targeting inflammatory crosstalk between tumors and their microenvironment has emerged as a crucial method for suppressing pancreatic adenocarcinoma (PAAD) progression. Berberine (BBR) is a natural pentacyclic isoquinoline alkaloid known for its anti-inflammatory and antitumor pharmacological effects; however, the mechanism underlying PAAD suppression remains unclear. We aim to investigate the effects of BBR on PAAD progression and their underlying mechanisms. METHODS: The prognostic value of inflammation-related genes in PAAD was assessed using bioinformatics analyses, then the pharmacological effects and potential mechanisms of BBR on PAAD will be investigated in silico, in vitro, and in vivo. RESULTS: Fifty-eight prognostic inflammation-related genes were identified in PAAD, which were shown to have good sensitivity and specificity using a novel inflammation-related gene risk-prognosis prediction model. Among these, four candidate genes (CAPS3, PTGS2, ICAM1, and CXCR4) were predicted as targets of BBR in PAAD in silico. Molecular docking simulations showed that the four key targets docked well with BBR. Further BBR treatment suppressed cell proliferation, colony formation, and induced cell cycle arrest in vitro. Moreover, BBR exhibited a significant tumor-suppressive effect in murine subcutaneous xenografts without macroscopic hepatic and renal toxicities. In addition, BBR downregulated CAPS3, PTGS2, ICAM1, and CXCR4 protein expression. CONCLUSION: This study not only elucidated the prognostic value of inflammation-related genes in PAAD but also demonstrated the potential of BBR to inhibit PAAD by targeting these genes.

Evidence-Based Dampness-Heat ZHENG (Syndrome) in Cancer: Current Progress toward Establishing Relevant Animal Model with Pancreatic Tumor.

Cancer is one of the deadliest diseases affecting the health of human beings. With limited therapeutic options available, complementary and alternative medicine has been widely adopted in cancer management and is increasingly becoming accepted by both patients and healthcare workers alike. Chinese medicine characterized by its unique diagnostic and treatment system is the most widely applied complementary and alternative medicine. It emphasizes symptoms and ZHENG (syndrome)-based treatment combined with contemporary disease diagnosis and further stratifies patients into individualized medicine subgroups. As a representative cancer with the highest degree of malignancy, pancreatic cancer is traditionally classified into the "amassment and accumulation". Emerging perspectives define the core pathogenesis of pancreatic cancer as "dampness-heat" and the respective treatment "clearing heat and resolving dampness" has been demonstrated to prolong survival in pancreatic cancer patients, as has been observed in many other cancers. This clinical advantage encourages an exploration of the essence of dampness-heat ZHENG (DHZ) in cancer and investigation into underlying mechanisms of action of herbal formulations against dampness-heat. However, at present, there is a lack of understanding of the molecular characteristics of DHZ in cancer and no standardized and widely accepted animal model to study this core syndrome in vivo. The shortage of animal models limits the ability to uncover the antitumor mechanisms of herbal medicines and to assess the safety profile of the natural products derived from them. This review summarizes the current research on DHZ in cancer in terms of the clinical aspects, molecular landscape, and animal models. This study aims to provide comprehensive insight that can be used for the establishment of a future standardized ZHENG-based cancer animal model.

HELLS serves as a poor prognostic biomarker and its downregulation reserves the malignant phenotype in pancreatic cancer.

BACKGROUND: SMARCAs, belonged to SWI/SNF2 subfamilies, are critical to cellular processes due to their modulation of chromatin remodeling processes. Although SMARCAs are implicated in the tumor progression of various cancer types, our understanding of how those members affect pancreatic carcinogenesis is quite limited and improving this requires bioinformatics analysis and biology approaches. METHODS: To address this issue, we investigated the transcriptional and survival data of SMARCAs in patients with pancreatic cancer using ONCOMINE, GEPIA, Human Protein Atlas, and Kaplan-Meier plotter. We further verified the effect of significant biomarker on pancreatic cancer in vitro through functional experiment. RESULTS: The Kaplan-Meier curve and log-rank test analyses showed a positive correlation between SMARCA1/2/3/SMARCAD1 and patients' overall survival (OS). On the other hand, mRNA expression of SMARCA6 (also known as HELLS) showed a negative correlation with OS. Meanwhile, no significant correlation was found between SMARCA4/5/SMARCAL1 and tumor stages and OS. The knockdown of HELLS impaired the colony formation ability, and inhibited pancreatic cancer cell proliferation by arresting cells at S phase. CONCLUSIONS: Data mining analysis and cell function research demonstrated that HELLS played oncogenic roles in the development and progression of pancreatic cancer, and serve as a poor prognostic biomarker for pancreatic cancer. Our work laid a foundation for further clinical applications of HELLS in pancreatic cancer.

Corrigendum: ß-Sitosterol and Gemcitabine Exhibit Synergistic Anti-Pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial-Mesenchymal Transition by Deactivating Akt/GSK-3ß Signaling.

[This corrects the article DOI: 10.3389/fphar.2018.01525.].

ß-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial-Mesenchymal Transition by Deactivating Akt/GSK-3ß Signaling.

ß-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial-mesenchymal transition (EMT) markers and AKT/GSK-3ß signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.