Pancreatic cancer is the fourth leading cause of cancer‐related death in the United States. Reactive oxygen species (ROS) are generally increased in pancreatic cancer cells compared with normal cells. ROS plays a vital role in various cellular biological activities including proliferation, growth, apoptosis, and invasion. Besides, ROS participates in tumor microenvironment orchestration. The role of ROS is a doubled‐edged sword in pancreatic cancer. The dual roles of ROS depend on the concentration. ROS facilitates carcinogenesis and cancer progression with mild‐to‐moderate elevated levels, while excessive ROS damages cancer cells dramatically and leads to cell death. Based on the recent knowledge, either promoting ROS generation to increase the concentration of ROS with extremely high levels or enhancing ROS scavenging ability to decrease ROS levels may benefit the treatment of pancreatic cancer. However, when faced with oxidative stress, the antioxidant programs of cancer cells have been activated to help cancer cells to survive in the adverse condition. Furthermore, ROS signaling and antioxidant programs play the vital roles in the progression of pancreatic cancer and in the response to cancer treatment. Eventually, it may be the novel target for various strategies and drugs to modulate ROS levels in pancreatic cancer therapy.

Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis.

Activation of pancreatic stellate cells (PSCs) initiates pancreatic fibrosis in chronic pancreatitis and furnishes a niche that enhances the malignancy of pancreatic cancer cells (PCCs) in pancreatic ductal adenocarcinoma (PDAC). Resveratrol (RSV), a natural polyphenol, exhibits potent antioxidant and anticancer effects. However, whether and how RSV influences the biological properties of activated PSCs and the effects of these changes on tumor remain unknown. In the present study, we found that RSV impeded hydrogen peroxide‐driven reactive oxygen species‐ (ROS‐) induced activation, invasion, migration, and glycolysis of PSCs. In addition, miR‐21 expression in activated PSCs was downregulated after RSV treatment, whereas the PTEN protein level increased. miR‐21 silencing attenuated ROS‐induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR‐21 rescued the responses of PSCs treated with RSV. Moreover, RSV or N‐acetyl‐L‐cysteine (NAC) administration or miR‐21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR‐21 upregulation. Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR‐21‐mediated activation and glycolysis in PSCs. Therefore, targeting miR‐21‐mediated glycolysis by RSV in tumor stroma may serve as a new strategy for clinical PDAC prevention or treatment.

Diabetes mellitus (DM) and pancreatic cancer are intimately related, as approximately 85% of patients diagnosed with pancreatic cancer have impaired glucose tolerance or even DM. Our previous studies have indicated that high glucose could promote the invasive and migratory abilities of pancreatic cancer cells. We therefore explored the underlying mechanism that hyperglycemia modulates the metastatic potential of pancreatic cancer. Our data showed that streptozotocin‐ (STZ‐) treated diabetic nude mice exhibit larger tumor size than that of the euglycemic mice. The number of nude mice that develop liver metastasis or ascites is much more in the STZ‐treated group than that in the euglycemic group. Hyperglycemic mice contain a higher plasma H₂O₂‐level than that from euglycemic mice. The injection of polyethylene glycol‐conjugated catalase (PEG‐CAT), an H₂O₂ scavenger, may reverse hyperglycemia‐induced tumor metastasis. In addition, hyperglycemia could also modulate the expression of epithelial‐mesenchymal transition‐ (EMT‐) related factors in pancreatic tumor tissues, as the E‐cadherin level is decreased and the expression of mesenchymal markers N‐cadherin and vimentin as well as transcription factor snail is strongly increased. The injection of PEG‐CAT could also reverse hyperglycemia‐induced EMT. These results suggest that the association between hyperglycemia and poor prognosis of pancreatic cancer can be attributed to the alterations of EMT through the production of hydrogen peroxide.

Background: Gastric Cancer (GC) is one of the most malignant and lethal tumors worldwide. The hypoxic microenvironment is correlated with GC cell invasion, metastasis and Epithelial-Mesenchymal Transition (EMT). Resveratrol is a compound extracted from various plants, including grapes, berries, and some traditional Chinese medicines. Recently, the anticancer properties of resveratrol against many cancers have been reported in a range of studies. However, the exact mechanism through which resveratrol prevents GC invasion and metastasis under hypoxic conditions remains unclear. Objective: The objective of this study is to show to what extent resveratrol could inhibit the hypoxia-induced malignant biological behavior of GC. Methods: SGC-7901 cells were cultured in a consistent 3% O2 hypoxic condition or 21% O2 normal condition for 48 hours to establish an in vitro hypoxia model. Western blot and qRT-PCR were used to detect EMT markers of SGC- 7901 cells, including E-cadherin, HIF-1a, Vimentin, etc. Transwell Matrigel Invasion Assays were used to test the invasive ability of SGC-7901 cells. The siRNA targeting Gli-1 showed its role in hypoxia-induced EMT and invasion of SGC-7901 cells. Results: Resveratrol was found to significantly decrease HIF-1α protein levels induced by hypoxia in SGC-7901 cells. HIF-1α accumulation was found to promote cell proliferation, migration, and invasive capacities in addition to EMT changes through the activation of the Hedgehog pathway. These effects were found to be reversed by resveratrol. Conclusion: Therefore, these data indicate that resveratrol may serve as a potential anticancer agent for the treatment of GC, even in a hypoxic tumor microenvironment.