Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

Abstract

Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFkB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/b-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. Cancer Prev Res; 7(4); 388-97. Ó2014 AACR.

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

“…However, the possibility of additive or synergistic exposure of drugs and DSs with AMPK agonist activity deserves further study in vitro and in vivo. This is especially true since AMPK agonists can both activate the enzyme through the positive regulatory Ύ-subunit and by inactivating the negative regulatory β-subunit, causing supramaximal effects [38,39,103].…”

“…But, many DSs or drugs may have additive effects that supersede the beneficial dose range into the toxic range. Many DSs and drugs may have supramaximal effects in regulation of cancer cells and an impact in the liver [37][38][39]. Additive effects could be from simultaneous exposure or sequential exposure due to dietary or drug consumption.…”

Simultaneous Application of Photothermal Therapy and an Anti‐inflammatory Prodrug using Pyrene–Aspirin‐Loaded Gold Nanorod Graphitic Nanocapsules

“…[10] However,t he lack of specific targets and individual pharmacokinetics hinders the administration of free-drug formulations.These problems can be solved through synthesizing an aspirin prodrug and delivering it by nanomaterials.H ere,t he 1-Pyrene methanol molecule,w hich could anchor on the graphitic surface of AuNR@G, [11] was utilized to facilitate aspirin delivery by synthesizing ap rodrug,p yrene-aspirin (P-aspirin). P-aspirin can be released from AuNR@G during PTT near the heating center to deliver its anti-inflammatory effect.…”

Chronic Pancreatitis as an Inductor of Pancreatic Cancer — Correlations With Inflammatory Pathways

“…Sclabas et al showed that aspirin inhibits the activation of the NF-kB pathway in cultured cells and decreased the expression of the COX-2 gene [42,64]. Moreover, aspirin may activate adenosine monophosphate-activated protein kinase (AMPK), and may affect Notch, Wnt/β-catenin, and other signalling pathways [65]. Nimesulide (4-nitro-2 phenoxymethanesulfonanilide), another NSAID, significantly decreases PDA in mice treated during the postinitiation phase of pancreatic carcinogenesis [66].…”