Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural
Marta Cykowiak1, Robert Kleszcz1, Małgorzata Kucińska2
1Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, 4, Święcickiego Street, 60-781 Poznań, Poland.
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.
Insights
This study explored phytochemical combinations for pancreatic cancer therapy. Xanthohumol and phenethyl isothiocyanate combination effectively modulated Nrf2 and NF-κB pathways, showing therapeutic promise.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic cancer involves signaling pathway deregulation, necessitating novel therapeutic strategies.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB) pathways are critical in cancer progression.
- Phytochemicals offer potential as modulators of these key cancer pathways.
Purpose of the Study:
- To investigate the effects of phytochemical combinations on Nrf2 and NF-κB pathways in pancreatic cancer cells.
- To compare the efficacy of single compounds versus combinations in modulating cancer cell signaling.
- To assess the anti-inflammatory and pro-apoptotic effects of these phytochemicals in vitro and in vivo.
Main Methods:
- Utilized PSN-1 (pancreatic cancer) and MS1 (non-cancerous) cell lines for comparative analysis.
- Evaluated canonical and non-canonical Nrf2 activation and NF-κB pathway signaling.
- Assessed target gene expression, cell survival, and tumor burden in xenograft mouse models.
Main Results:
- PSN-1 cells exhibited higher sensitivity to tested compounds than MS1 cells.
- The combination of xanthohumol and phenethyl isothiocyanate demonstrated superior Nrf2 pathway modulation compared to single agents.
- Reduced NF-κB activation, decreased COX-2 and STAT3 levels, and partial tumor response in vivo were observed.
Conclusions:
- The combination of xanthohumol and phenethyl isothiocyanate shows significant potential for modulating key cancer pathways.
- This phytochemical combination exhibits anti-inflammatory and pro-apoptotic properties relevant to pancreatic cancer treatment.
- Further investigation into xanthohumol and phenethyl isothiocyanate as therapeutic candidates for pancreatic cancer is warranted.
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