Combinations of Phytochemicals More Efficiently than Single Components Activate Nrf2 and Induce the Expression of Antioxidant Enzymes in Pancreatic Cancer Cells

Abstract

Cancer prevention particularly related to aging can be improved by the use of phytochemicals combinations. In this study, we evaluated the effect of phenethyl isothiocyanate (PEITC), xanthohumol (XAN), indole-3-carbinol (I3C), and resveratrol (RES) and their combinations on the Nrf2 signaling pathway. Human pancreatic cancer cells MIA-Pa-Ca-2 were treated with the phytochemicals alone or their equimolar mixture for 24 h and activation of Nrf2 and expression of its target genes were evaluated. Phytochemicals alone enhanced Nrf2 activation and expression, but their combinations were more efficient. The mixture of XAN and PEITC was found to be the most potent modulator of the Nrf2 pathway. Moreover, increased levels of P-Nrf2 and P-JNK and decreased level of P-GSK-3β suggested possible activation of Nrf2 through modulation of these kinases. The combinations of XAN with PEITC and RES with PEITC increased mostly the expression of SOD, GSTP, CAT, and GPx. XAN and PEITC mixture induced the cell cycle arrest in G0/G1 phase and increased apoptotic and autophagy markers. These results indicate that combinations of phytochemicals resembling that occurring in natural diets may efficiently modulate the signaling pathways, which proper function is important for pancreatic cancer prophylaxis or improving the results of conventional therapy.

Disclosure Statement

No potential conflict of interest was reported by the author.

Additional information

Funding

This work was funded by Grant No. 2016/21/B/NZ5/01390 from the National Science Centre, Poland.

Notes on contributors

Marta Cykowiak

Marta Cykowiak: investigation, formal analysis, statistical analysis and preparing the figures. Violetta Krajka-Kuźniak: conceptualization, investigation, formal analysis, the data interpretation, project administration, preparing draft of manuscript. Wanda Baer-Dubowska: data interpretation and final writing. All authors read and approved the final manuscript.

Violetta Krajka-Kuźniak

Marta Cykowiak: investigation, formal analysis, statistical analysis and preparing the figures. Violetta Krajka-Kuźniak: conceptualization, investigation, formal analysis, the data interpretation, project administration, preparing draft of manuscript. Wanda Baer-Dubowska: data interpretation and final writing. All authors read and approved the final manuscript.

Wanda Baer-Dubowska

Marta Cykowiak: investigation, formal analysis, statistical analysis and preparing the figures. Violetta Krajka-Kuźniak: conceptualization, investigation, formal analysis, the data interpretation, project administration, preparing draft of manuscript. Wanda Baer-Dubowska: data interpretation and final writing. All authors read and approved the final manuscript.