xanthohumol and Pancreatic-Neoplasms

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

Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor-κB (NF-κB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF-κB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF-κB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC-3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC-3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki-67 expression, CD31-positive microvessel density, NF-κB p65 expression, and VEGF and IL-8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF-κB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coculture Techniques; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Mice; Pancreatic Neoplasms; Propiophenones; Transcription Factor RelA; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Pancreatic cancer remains a lethal disease with limited treatment options. At the time of diagnosis, approximately 80% of these patients present with unresectable tumors caused by either locally advanced lesions or progressive metastatic growth. Therefore, development of novel treatment strategies and new therapeutics is needed. Xanthohumol (XN) has emerged as a potential compound that inhibits various types of cancer, but the molecular mechanism underlying the effects of XN remains unclear. In the present study, we have assessed the efficacy of XN on pancreatic cancer cell lines (AsPC-1, PANC-1, L3.6pl, MiaPaCa-2, 512, and 651) against cell growth in real time and using colony-forming assays. Treatment with XN resulted in reduction in cellular proliferation in a dose- and time-dependent manner. The growth suppression effect of XN in pancreatic cancer cell lines is due to increased apoptosis via the inhibition of the Notch1 signaling pathway, as evidenced by reduction in Notch1, HES-1, and survivin both at mRNA as well as protein levels. Notch1 promoter reporter analysis after XN treatment indicated that XN downregulates Notch promoter activity. Importantly, overexpression of active Notch1 in XN-treated pancreatic cancer cells resulted in negation of growth suppression. Taken together, these findings demonstrate, for the first time, that the growth suppressive effect of XN in pancreatic cancer cells is mainly mediated by Notch1 reduction.

Topics: Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Flavonoids; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Inhibitor of Apoptosis Proteins; Pancreatic Neoplasms; Propiophenones; Receptor, Notch1; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Survivin; Time Factors; Transcription Factor HES-1; Tumor Stem Cell Assay

Pancreatic cancer (PC) is one of the most lethal human malignancies worldwide. Here, we demonstrated that xanthohumol (XN), the most abundant prenylated chalcone isolated from hops, inhibited the growth of cultured PC cells and their subcutaneous xenograft tumors. XN treatment was found to induce cell cycle arrest and apoptosis of PC cells (PANC-1, BxPC-3) by inhibiting phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of its downstream targeted genes cyclinD1, survivin, and Bcl-xL at the messenger RNA level, which involved in regulation of apoptosis and the cell cycle. Overall, our results suggested that XN presents a promising candidate therapeutic agent against human PC and the STAT3 signaling pathway is its key molecular target.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chalcone; Dose-Response Relationship, Drug; Flavonoids; Humans; Humulus; Mice; Mice, Nude; Pancreatic Neoplasms; Prenylation; Propiophenones; Xenograft Model Antitumor Assays