Aspirin Regulates Gemcitabine Resistance in Pancreatic Cancer via Inhibiting the PI3K/Akt/mTOR Signaling Pathway and Reversing Epithelial-mesenchymal Transition

Abstract

Background: Gemcitabine is considered a classical agent for the treatment of patients with pancreatic cancer. However, gemcitabine resistance is a common cause of treatment failure, leading to poor survival. Therapy to overcome gemcitabine resistance would benefit patients with pancreatic cancer. This study investigated the impact of aspirin (ASA) to gemcitabine resistance in the biological function of pancreatic cancer cells and the potential mechanism. Methods: The MTT assay, wound healing assay and annexin V-FITC/PI test was used to determine whether ASA could inhibit gemcitabine resistance in pancreatic cancer cells. Besides, the expression of Bcl-2, Bax, E-cadherin, Vimentin, p-PI3K, p-AKT and p-mTOR was detected by the Western blot. Statistically significant differences between groups were determined with the Student’s t-test. Results: The proliferation and migration of SW1990 and BxPC3 cells were significantly decreased while the apoptosis rate was increased in the combination of ASA and gemcitabine group (p<0.05). The level of Bcl-2 was decreased and the level of Bax was increased significantly in the combination of ASA and gemcitabine group (p<0.05) while the level of p-PI3K, p-AKT and p-mTOR was decreased (p<0.05). What’s more, this group significantly reversed EMT in SW1990 and BxPC3 cells with an increase in the expression of E-cadherin and a decrease in Vimentin. Conclusion: Our research provided evidence ASA could help to inhibit gemcitabine resistance of pancreatic cancer cells, probably via inhibiting the PI3K/AKT/mTOR pathway and reversing EMT. Thus, combined use of ASA and gemcitabine is expected to be a potential therapeutic strategy for pancreatic cancer patients.

Repositioning of Old Drugs for Novel Cancer Therapies: Continuous Therapeutic Perfusion of Aspirin and Oseltamivir Phosphate with Gemcitabine Treatment Disables Tumor Progression, Chemoresistance, and Metastases

“…Aberrant PI3K/Akt activation may promote the survival and proliferation of tumor cells in many human cancers [ 46 , 47 , 48 ]. ASA has been reported to inhibit the PI3K/Akt/mTOR signaling pathway to mitigate GEM resistance and EMT in pancreatic cancer cells [ 49 ]. ASA was also reported to inhibit protein expression levels of PI3K, p-Akt significantly, and p-mTOR in PANC-1 cells compared to untreated controls [ 50 ].…”

“…Interestingly, all treatments decreased PI3K expression except for PUMP (OP) in combination with GEM ( Figure 5 A,D). To explain this later result, it is noteworthy that all treatment regimens had ASA except for the PUMP (OP) and GEM combination, which may be due to ASA’s unique inhibition of the PI3K/Akt/mTOR signaling pathway to mitigate GEM resistance [ 49 ]. Additionally, the significant increase in PI3K expression following PUMP (OP) and GEM treatment may be due to the specific targeting and activation of altered EGFRs by OP, as previously reported by us [ 34 ].…”