Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural Compounds

Abstract

Pancreatic cancer is a disease in which deregulation of signaling pathways plays a key role, thus searching for their novel modulators is a promising therapeutic strategy. Hence, in this study, the effect of phytochemical combinations on the canonical and non-canonical activation of Nrf2 and its interaction with the NF-κB pathway was evaluated in extensively proliferating pancreatic cancer cell line, PSN-1, in comparison to non-cancerous MS1 cells. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cell survival were assessed in PSN-1 cells. The tumor burden was evaluated in mice carrying xenografts. PSN-1 cells were more sensitive to the tested compounds as compared to the MS1 cell line. Combination of xanthohumol and phenethyl isothiocyanate was more effective than single compounds at decreasing the canonical and non-canonical activation of Nrf2 in PSN-1 cancer cells. Decreased activation of NF-κB, and subsequent reduced cytosolic COX-2 and nuclear STAT3 level indicated their anti-inflammatory and pro-apoptotic activities. In vivo studies showed the partial response in groups treated with xanthohumol or the combination of xanthohumol and phenethyl isothiocyanate. Overall, these results suggest that the combination of xanthohumol and phenethyl isothiocyanate may be a promising therapeutic candidate against pancreatic cancer.

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“…These compounds exhibited anticarcinogenic activities in in vivo experiments [24][25][26][27][28][29][30][31][32] or on human colon cancer cells [33]. PEITC also exhibited anticarcinogenic activities [34][35][36]. Thus, these results should be investigated further for the anticarcinogenic properties of BUITC and PEN in in vivo experiments.…”

Identification of characteristic markers correlated with Th2 cell infiltration and metabolism molecular subtype in pancreatic adenocarcinoma

“…In addition, cellular processes, including apoptosis, ferroptosis, necroptosis ( 29 ), and autophagy ( 30 ), have been shown to affect the tumor immune microenvironment of pancreatic adenocarcinoma. Multiple signal transduction pathways, including Wnt ( 31 ), vascular endothelial growth factor (VEGF) ( 32 ), transforming growth factor (TGF)-beta ( 31 ), PI3K-Akt ( 33 ), nuclear factor (NF)-kappa B ( 34 ) and hedgehog ( 35 ), have been shown to participate in the growth and metastasis of pancreatic adenocarcinoma and may be associated with immune infiltration. Based on the experimental outcome and prognostic significance, hub genes downstream of Th2 cells were investigated to explore their role in immunity, metabolism, cellular processes and signal transduction.…”

The therapeutic potential of natural products for treating pancreatic cancer

“…could inhibit the PSN-1 cell growth with an IC 50 46 µM and inhibit the MS1 cell growth with an IC 50 49 µM. This combination could greatly reduce the expression of NF-κB p65 subunits, and activate Nrf2 and downstream genes as GSTP, NQO1, and SOD in PANC-1 cells ( Krajka-Kuźniak et al, 2020 ) and PSN-1 cells ( Cykowiak et al, 2021 ). Further investigation revealed that the combination of xanthohumol (40 mg/kg) and phenethyl isothiocyanate (15 mg/kg) could inhibit the plasma COX-2 and nuclear STAT3 expression ( Cykowiak et al, 2021 ).…”