xanthohumol and phenethyl-isothiocyanate

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cyclooxygenase 2 Inhibitors; Down-Regulation; Drug Combinations; Flavonoids; Hep G2 Cells; Hepatoblastoma; Humans; Isothiocyanates; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Propiophenones; Signal Transduction; Superoxide Dismutase; Tumor Burden; Xenograft Model Antitumor Assays

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.

Topics: Animals; Apoptosis; Biological Products; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2; Drug Synergism; Flavonoids; Humans; Isothiocyanates; Mice; NF-E2-Related Factor 2; NF-kappa B; Pancreatic Neoplasms; Phytochemicals; Propiophenones; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Phytochemicals such as phenethyl isothiocyanate (PEITC), indole-3-carbinol (I3C), xanthohumol (XAN), and resveratrol (RES) have been shown to target signaling pathways that are involved in the proliferation and survival of different pancreatic cancer (PC) cell lines. While the activity of these compounds alone was extensively studied, their combinations were never assessed. Thus, the aim of this study was to evaluate and compare the effect of PEITC, I3C, XAN, and RES and their combinations on the expression and activation of NF-κB and Nrf2 in human PC cell line PANC-1. The combination of XAN and PEITC was more efficient than the single compounds in reducing the binding of NF-κB p65 subunits to DNA by 47-60% and expression of p65 gene by 28-48%. The combination of XAN and PEITC also enhanced the activation and expression of Nrf2 and subsequently the expression of GSTP, NQO1, and SOD genes which are controlled by this transcription factor. Modulation of the activity of NF-κB and Nrf2 by the combination of XAN and PEITC was found to lead to reduced proliferation of PANC-1 cells. These results suggest that the combination of XAN and PEITC might be considered as a novel strategy for the prophylaxis and/or treatment of PC.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Flavonoids; Humans; Indoles; Isothiocyanates; NF-E2-Related Factor 2; NF-kappa B; Pancreatic Neoplasms; Propiophenones; Resveratrol