CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling

Abstract

The mTOR signaling pathway is abnormally activated in pancreatic cancer and is related to tumor glucose metabolism. However, its specific regulation mechanism is still unclear. Therefore, this study aims to investigate whether Sestrin2 affects the glucose metabolism of pancreatic cancer by modulating mTOR signal and then affects its biological behavior. We have observed that l-leucine can promote the proliferation of pancreatic cancer cells and increase the expression of Sestrin2 and p-mTOR proteins. In order to further study the role of Sestrin2 and mTOR signaling in pancreatic cancer, we conducted Sestrin2 overexpression and mTOR pharmacological inhibition experiments. We found that Sestrin2 overexpression can increase glycolysis of pancreatic cancer cells and promote their proliferation. This effect can be eliminated by mTOR inhibitors. Finally, we found that Sestrin2 knockdown could inhibit the growth of pancreatic cancer in vivo. In conclusion, these findings suggest that Sestrin2 may promote the occurrence and development of pancreatic cancer through mTOR signaling.

Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing

“…Onatasertib (CC-223, DB12570) is an orally available, low nanomolar inhibitor of mTOR (IC 50 = 10 nM) [ 156 ], with putative antineoplastic activity [ 133 , 157 , 158 ]. The inhibition of mTOR by Onatasertib has been reported to induce tumor cell apoptosis and to decrease tumor cell proliferation [ 124 , 159 , 160 , 161 ]. Onatasertib is currently in phase II trials for the treatment of multiple myeloma, non-Hodgkin’s lymphoma ( ID: NCT01177397), and hepatocellular carcinoma ( ID: NCT03591965) and is in phase I trials for non-small-cell lung cancer ( ID: NCT01545947).…”

Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway

“…and plays a significant role in the tumorigenesis of pancreatic carcinoma [ 36 ]. It is abnormally activated in pancreatic cancer and is related to tumor glycolysis (Warburg effect) and other glucose metabolism process [ 37 ]. In addition, the mTOR signaling pathway also promotes gemcitabine resistance in PC.…”

A paradoxical role for sestrin 2 protein in tumor suppression and tumorigenesis

“…Additionally, the knockdown of sestrin 2 inhibited the growth of pancreatic cancer in vivo. This latter study indicated that the mTOR signaling pathway participated in sestrin 2-mediated promotion and development of pancreatic cancer [ 82 ].…”