Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. PDAC cell specific targeting of DZ-SIM is measured by determining the fluorescence in cells and animals. Mitochondrial bioenergetics and functions are measured by Seahorse and flow cytometry, respectively. Apoptosis is assessed by DNA fragmentation, annexin V/propidium iodide staining, and TUNEL. Markers of cell invasion, epithelial-to-mesenchymal transition, and cancer stemness are measured. The effect of DZ-SIM on survival, tumor growth, and metastasis is measured in the Kras þ/LSLG12D ;Trp53 þ/LSLR172H ;Pdx-1 −Cre transgenic mice and in syngeneic and subcutaneous PDAC models. NIR fluorescence imaging shows specific localization of DZ-SIM to cancer, but not to normal cells and tissues. DZ-SIM significantly inhibits tumor growth and re-sensitizes therapeutically resistant PDAC cells to conventional therapies. DZ-SIM kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics, including oxygen consumption and ATP production, and increasing ROS production. Mitochondrial depletion prevents the effect of DZ-SIM. Administration of DZ-SIM in three PDAC animal models results in a marked increase in survival and a decrease in tumor growth and metastasis.
Glycogen synthase kinase 3 beta (GSK-3β) is a serine/threonine protein kinase involved in multiple normal and pathological cell functions, including cell signalling and metabolism. GSK-3β is highly expressed in the onset and progression of multiple cancers with strong involvement in the regulation of proliferation, apoptosis, and chemoresistance. Multiple studies showed pro- and anti-cancer roles of GSK-3β creating confusion about the benefit of targeting GSK-3β for treating cancer. In this mini-review, we focus on the role of GSK-3β in pancreatic cancer. We demonstrate that the proposed anti-cancer roles of GSK-3β are not relevant to pancreatic cancer, and we argue why GSK-3β is, indeed, a very promising therapeutic target in pancreatic cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.