ABSTRACT
Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.
ABSTRACT
Objectives: Inhibition of carbohydrate digestion enzymes (α-amylase and α-glucosidase) has been reported in studies as a therapeutic approach for the management or treatment of type 2 diabetes mellitus, owing to its potential to decrease postprandial hyperglycemia. The anti-diabetic potential of Allium sativum (also known as garlic) against diabetes mellitus has been established. Therefore, in this study, we assessed the antidiabetic potential of A. sativum using in vitro enzyme assays after which we explored computational modelling approach using the quantified GC-MS identities to unravel the key bioactive compounds responsible for the anti-diabetic potential. Methods: We used in vitro enzyme inhibition assays (α-amylase and α-glucosidase) to evaluate antidiabetic potential and subsequently performed gas chromatography-mass spectroscopy (GC-MS) to identify and quantify the bioactive compounds of the plant extract. The identified bioactive compounds were subjected to in silico docking and pharmacokinetic assessment. Results: A. sativum phenolic extract showed high dose-dependent inhibition of α-amylase and α-glucosidase (p < 0.05). Interestingly, the extract inhibited α-glucosidase with a half maximal inhibitory concentration of 53.75 µg/mL, a value higher than that obtained for the standard acarbose. Docking simulation revealed that morellinol and phentolamine were the best binders of α-glucosidase, with mean affinity values of -7.3 and -7.1 kcal/mol, respectively. These compounds had good affinity toward active site residues of the enzyme, and excellent drug-like and pharmacokinetic properties supporting clinical applications. Conclusions: Our research reveals the potential of A. sativum as a functional food for the management of type 2 diabetes, and suggests that morellinol and phentolamine may be the most active compounds responsible for this anti-diabetic prowess. Therefore these compounds require further clinical asessment to demonstrate their potential for drug development.
ABSTRACT
OBJECTIVES: Increasing evidence suggests that regular physical exercise improves type 2 diabetes mellitus (T2DM). However, the potential beneficial effects of swimming on insulin resistance and lipid disorder in T2DM, and its underlying mechanisms remain unclear. MATERIALS AND METHODS: Rats were fed with high fat diet and given a low dosage of Streptozotocin (STZ) to induce T2DM model, and subsequently treated with or without swimming exercise. An 8-week swimming program (30, 60 or 120 min per day, 5 days per week) decreased body weight, fasting blood glucose and fasting insulin. RESULTS: Swimming ameliorated lipid disorder, improved muscular atrophy and revealed a reduced glycogen deposit in skeletal muscles of diabetic rats. Furthermore, swimming also inhibited the activation of Wnt3a/ß-catenin signaling pathway, decreased Wnt3a mRNA and protein level, upregulated GSK3ß phosphorylation activity and reduced the expression of ß-catenin phosphorylation in diabetic rats. CONCLUSION: The trend of the result suggests that swimming exercise proved to be a potent ameliorator of insulin resistancein T2DM through the modulation of Wnt3a/ß-catenin pathway and therefore, could present a promising therapeutic measure towards the treatment of diabetes and its relatives.
