Autophagy Inhibitor (LY294002) and 5-fluorouracil (5-FU) Combination-Based Nanoliposome for Enhanced Efficacy Against Esophageal Squamous Cell Carcinoma

Abstract

In this study, 5-fluorouracil (5-FU) and LY294002 (LY)-loaded PEGylated nanoliposome was prepared to target esophageal squamous cell carcinoma (ESCC). The particles were characterized in terms of physicochemical and biological parameters. The co-delivery of autophagy inhibitor and chemotherapeutic drug in a single carrier was successfully accomplished. The two components from 5-FU and LY-loaded PEGylated nanoliposome (FLNP) released in a controlled manner with LY relatively released faster compared to that of 5-FU. FLNP showed a receptor-mediated cellular uptake that will allow the gradual release of drug in the acidic environment. The cellular uptake of nanoparticles (NP) was further confirmed by FACS analysis. The combination of 5-FU and LY resulted in higher cytotoxic effect compared to that of individual drugs. Most importantly, FLNP exhibited a significantly higher anticancer effect in cancer cells compared to that of free cocktail combinations. The faster release of LY from FLNP leads to autophagy inhibition that improves the sensitivity of cancer cells towards 5-FU, resulting in more cell death. Consistently, FLNP induced a greater apoptosis (~ 48%) of cancer cells compared to that of any other groups. Western blot analysis clearly showed that 5-FU and LY individually increased the expression of caspase-3 and PARP, while as expected FLNP induced a remarkable expression of these protein markers indicating the superior anticancer effect. We believe that the programmed release of autophagy inhibitor and chemotherapeutic drug from a single nanocarrier will increase the prospect of anticancer therapy in ESCC.

Prognostic significance of autophagy-related genes within esophageal carcinoma

“…Moreover, previous studies also indicate that ginsenoside Rk3 [ 30 ] and Sinoporphyrin sodium (DVDMs)-Photodynamic therapy (PDT) [ 31 ], which exert their functions by targeting autophagy, inhibit the survival of esophageal carcinoma cells. Furthermore, other studies also illustrate that the treatment targeting autophagy contributes to enhancing the anti-tumor effect [ 32 – 34 ], which functions based on the chemotherapy agents (cisplatin [ 33 ], 5-fluorouracil (5-FU) [ 34 ]).…”

Lipid-Based Nanoparticles: Application and Recent Advances in Cancer Treatment

“…This system determined an increased tumor growth inhibition, with no alterations of WBC, hemogram profile or weight loss. Another interesting approach, developed by Feng et al [59], was the use of PEG-LY294002 (autophagy inhibitor)-nanoliposome loaded with 5-FU. This nanoliposome made it possible to release the autophagy inhibitor more quickly, increasing the effect of 5-FU in a synergistic way, and achieving higher cell death rates in EC-9706 cells.…”

The Exploitation of Liposomes in the Inhibition of Autophagy to Defeat Drug Resistance

“…This liposomal formulation showed higher anticancer effect in cancer cells with respect to 5-FU treatment without liposomal formulation. Due to inhibition of autophagy by LY, the enhanced sensitivity of cancer cells to 5-FU was revealed (Feng et al, 2018).…”

“…-85 (Yin et al, 2018) EPC/DSPE-PEG/chol (10:4:1 molar ratio − total 10 mg) 5-FU: passive (10 mg)LY: passive (1.5 mg) 150 25 93 86 (Feng et al, 2018) SPC, Sphingosylphosphorylcholine; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine; EPC, egg phosphatidyl-choline; chol, cholesterol.…”