Landmarks in pancreatic cancer studies.

Pancreatic cancer is a rare but fatal disease. Patients present advanced disease due to the lack of or typical symptoms when the tumor is still localized. A high-quality image processing system has been in practice to detect the pancreatic tumor and determine the possibility of surgery, and preoperative methods, such as ERCP are increasingly used to complement the staging modality. Pancreaticoduodenectomy is one of the complicated surgeries with potential morbidity. The minimally invasive pancreatic resections, both robot-assisted and laparoscopic, have become a part of standard surgical practice worldwide over the last decade. Moreover, advancements in adjuvant chemotherapy have improved the long-term outcomes in current clinical practice. The systemic conservative treatment, including targeted agents, remains the mainstay of treatment for patients with advanced disease. An increasing number of studies are focused on modulating the pancreatic tumor microenvironment to improve the efficacy of the immunotherapeutic strategies. Herein, the role of preoperative therapy, the novel surgical strategy, and individualized systemic treatment in pancreatic cancer is investigated. Also, the randomized controlled studies that have defined the neoadjuvant and surgical management of pancreatic cancer have been summarized.

Antitumor Effects of Paeoniflorin on Hippo Signaling Pathway in Gastric Cancer Cells.

BACKGROUND: Paeoniflorin has been reported to exert antitumor effects on human cancers. However, the role of paeoniflorin in gastric cancer and the underlying molecular mechanism are unelucidated. Therefore, we determined whether paeoniflorin could exhibit anticancer activity in gastric cancer cells. METHODS: MTT was used to measure the viability of cells after paeoniflorin treatment. FACS was performed to examine cell apoptosis. Wound healing and transwell invasion assays were conducted to examine cell migratory and invasive activities. Western blotting was used to explore the mechanism by which paeoniflorin exerted tumor suppressive effects. RESULTS: We found that paeoniflorin suppressed cell growth, enhanced apoptosis, and reduced cell invasion. Notably, we showed that paeoniflorin inhibited the expression of TAZ in gastric cancer cells. The overexpression of TAZ abrogated the antitumor activity of paeoniflorin in gastric cancer cells. In contrast, the downregulation of TAZ promoted the tumor suppressive effects of paeoniflorin treatment. CONCLUSION: Hence, targeting TAZ with paeoniflorin could be a novel approach for the treatment of human gastric cancer.

Diosgenin Exerts Antitumor Activity via Downregulation of Skp2 in Breast Cancer Cells.

BACKGROUND: Breast cancer is the common malignancy with high morbidity and mortality in women. S-phase kinase-associated protein 2 (Skp2) has been characterized to play an oncogenic role in the breast carcinogenesis and progression. Therefore, inactivation of Skp2 in breast cancer might be a novel approach for fighting breast malignancy. A natural compound diosgenin has been reported to exert anticancer activity in a variety of human cancers. However, the underlying mechanism has not been fully determined. METHODS: In this study, we aim to explore whether diosgenin performed antitumor activity via inhibition of Skp2 in breast cancer cells using several methods including MTT, Transwell invasion assay, RT-PCR, western blotting, and transfection. RESULTS: We found that diosgenin inhibited cell viability and stimulated apoptosis. Moreover, we found that diosgenin reduced cell invasion in breast cancer cells. Furthermore, diosgenin inhibited the expression of Skp2 in breast cancer cells. Notably, diosgenin reduced cell viability and motility and induced apoptosis via suppression of Skp2 in breast cancer cells. CONCLUSION: Our findings revealed that diosgenin could be a potential inhibitor of Skp2 for treating breast cancer.

Downregulation of FoxM1 inhibits cell growth and migration and invasion in bladder cancer cells.

The FoxM1 (Forkhead Box M1) transcription factor plays a key role in regulation of cell growth, cell cycle, and transformation. Higher expression of FoxM1 has been observed in various types of human cancers including bladder cancer. However, the exact function of FoxM1 in bladder cancer has not been elucidated. To investigate the cellular and molecular function of FoxM1 in bladder cancer, we measured the consequences of downregulation and upregulation of FoxM1 in bladder cancer cells using MTT assay, wound healing assay, and invasion assay. We found that downregulation of FoxM1 inhibited cell growth, but induced apoptosis in bladder cancer cells. Moreover, we found that inhibition of FoxM1 retarded cell migration and invasion. In line with this, upregulation of FoxM1 led to cell growth promotion and inhibited cell apoptosis in bladder cancer cells. Consistently, upregulation of FoxM1 led to increased cell migration and invasion. Our Western blotting results identified that downregulation of FoxM1 increased p27 level and inhibited VEGF, while overexpression of FoxM1 reduced p27 level and increased VEGF. Our findings suggest that FoxM1 could be a useful target for the treatment of bladder cancer.

Nanoprodrug of retinoic acid-modified paclitaxel.

All-trans-retinoic acid (RA) is a non-toxic physiological metabolite of vitamin A. A paclitaxel (PTX) prodrug (RA-PTX) with high PTX content of 75% was synthesized via an easy condensation reaction. RA-PTX nanoparticles (RA-PTX NPs) were prepared through a nanoprecipitation method which increased the water solubility of PTX. RA-PTX NPs were spherical in shape and exhibited favorable structural stability in both water and the physiological environment. RA-PTX NPs possessed effective cellular uptake as revealed by confocal laser scanning microscopy and exerted potent cytotoxicity. These results highlight the potential of nanomedicines from PTX prodrugs for increasing the drug loading and water solubility of PTX.

Santamarine Inhibits NF-κB Activation and Induces Mitochondrial Apoptosis in A549 Lung Adenocarcinoma Cells via Oxidative Stress.

Santamarine (STM), a sesquiterpene lactone component of Magnolia grandiflora and Ambrosia confertiflora, has been shown to possess antimicrobial, antifungal, antibacterial, anti-inflammatory, and anticancer activities. However, no study has yet been conducted to investigate the molecular mechanism of STM-mediated anticancer activity. In the present study, we found that STM inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells through induction of oxidative stress. STM induces oxidative stress by promoting reactive oxygen species (ROS) generation, depleting intracellular glutathione (GSH), and inhibiting thioredoxin reductase (TrxR) activity in a dose-dependent manner. Further mechanistic study demonstrated that STM induces apoptosis by modulation of Bax/Bcl-2 expressions, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of PARP in a dose-dependent manner. Moreover, STM inhibited the constitutive and inducible translocation of NF-κBp65 into the nucleus. IKK-16 (I-κB kinase inhibitor) augmented the STM-induced apoptosis, indicating that STM induces apoptosis in A549 cells at least in part through NF-κB inhibition. Finally, STM-induced apoptosis and expressions of apoptosis regulators were effectively inhibited by thiol antioxidant N-acetyl-L-cysteine (NAC), indicating that STM exerts its anticancer effects mainly through oxidative stress. To the best of our knowledge, this is the first report providing evidence of anticancer activity and molecular mechanism of STM.

MiR-26b reverses temozolomide resistance via targeting Wee1 in glioma cells.

Emerging evidence has demonstrated that microRNAs (miRNA) play a critical role in chemotherapy-induced epithelial-mesenchymal transition (EMT) in glioma. However, the underlying mechanism of chemotherapy-triggered EMT has not been fully understood. In the current study, we determined the role of miR-26b in regulation of EMT in stable temozolomide (TMZ)-resistant (TR) glioma cells, which have displayed mesenchymal features. Our results illustrated that miR-26b was significantly downregulated in TR cells. Moreover, ectopic expression of miR-26b by its mimics reversed the phenotype of EMT in TR cells. Furthermore, we found that miR-26b governed TR-mediate EMT partly due to governing its target Wee1. Notably, overexpression of miR-26b sensitized TR cells to TMZ. These findings suggest that upregulation of miR-26b or targeting Wee1 could serve as novel approaches to reverse chemotherapy resistance in glioma.

Antitumor activity of curcumin is involved in down-regulation of YAP/TAZ expression in pancreatic cancer cells.

Pancreatic cancer (PC) is one of the most aggressive human malignancies worldwide and is the fourth leading cause of cancer-related deaths. Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Certain studies have demonstrated that curcumin exerts its anti-tumor function in a variety of human cancers including PC, via targeting multiple therapeutically important cancer signaling pathways. However, the detailed molecular mechanisms are not fully understood. Two transcriptional co-activators, YAP (Yes-associated protein) and its close paralog TAZ (transcriptional coactivator with PDZ-binding motif) exert oncogenic activities in various cancers. Therefore, in this study we aimed to determine the molecular basis of curcumin-induced cell proliferation inhibition in PC cells. First, we detected the anti-tumor effects of curcumin on PC cell lines using CTG assay, Flow cytometry, clonogenic assay, wound healing assay and Transwell invasion assay. We found that curcumin significantly suppressed cell growth, weakened clonogenic potential, inhibited migration and invasion, and induced apoptosis and cell cycle arrest in PC cells. We further measured that overexpression of YAP enhanced cell proliferation and abrogated the cytotoxic effects of curcumin on PC cells. Moreover, we found that curcumin markedly down-regulated YAP and TAZ expression and subsequently suppressed Notch-1 expression. Collectively, these findings suggest that pharmacological inhibition of YAP and TAZ activity may be a promising anticancer strategy for the treatment of PC patients.