The effect of resveratrol and its methylthio-derivatives on EGFR and Stat3 activation in human HaCaT and A431 cells

Epidermal growth factor receptor (EGFR) interacting with Stat3 is considered to be an attractive therapeutic target. In the current study, we investigated the effect of resveratrol and its two 4′-methylthio-trans-stilbene derivatives (3-M-4′-MTS; S2) (3,5-DM-4″-MTS; S5) on EGFR and Stat3 activation in human immortalized HaCaT keratinocytes and epidermoid carcinoma A431 cells. In the HaCaT cells both derivatives, similarly as resveratrol, decreased the total level of the EGFR receptor. In the A431 cells, resveratrol in the higher dose significantly (p < 0.05) reduced Y1173 and Y1068 EGFR residue phosphorylation, while S2 affected only the phosphorylation of the Y1068 residue. In this cell line, resveratrol in both tested doses and the S2 derivative in the lower concentration significantly diminished Stat3 binding capacity to the DNA consensus site. The effect of the tested compounds on Stat3 activation in HaCaT cells was only slightly affected. These results indicate that methylthiostilbenes are not more potent modulators of the EGFR/Stat3 complex than resveratrol and that introducing an additional methoxy group makes them less effective

Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2

© 2017 The Authors. Published by Nature Publishing Group. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/cddis.2017.176Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34(+)/CD38(+) leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34(+) AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34(+)/CD38(+) leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML

Glucosinolates and isothiocyanates: cancer preventive effects

The anticarcinogenic bioactivity of various isothiocyanates (ITCs) has been demonstrated in various animal models such as rats, mice, and hamsters, and in different target tissues such as lung, esophagus, and forestomach. A major chemopreventive mechanism of ITCs involves suppression of reactive metabolite generation and, therefore, a decrease in DNA adducts formation. Many in vitro studies have reported the effects of ITCs on cell cycle modulation and proapoptotic effects through a number of targets, at different points of the pathways. A comparative study in human subjects showed that the hydrolysis of glucosinolates and the absorption of ITCs are greater following ingestion of raw brassica with active plant myrosinase than after consumption of the cooked plant with denatured myrosinase. Apoptosis is considered a vital component of the cellular mechanisms responsible for the maintenance of homeostasis in multicellular organisms. Understanding the pathways of associated proteins provides an insight into the induction of apoptosis by anticancer agents

Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context

Role of Nrf2 in Pancreatic Cancer

Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor Erythroid 2-Related Factor 2/NFE2L2 (Nrf2) and its negative regulator Kelch-Like ECH-Associated Protein 1 (Keap1) provide substantial protection against damage induced by oxidative stress, and a growing body of evidence points to the canonical and noncanonical Nrf2 signaling pathway as a pharmacological target in the treatment of pancreatic diseases. In this review, we present updated evidence on the activation of the Nrf2 signaling pathway and its importance in pancreatic cancer. Our review covers potential modulators of canonical and noncanonical pathway modulation mechanisms that may have a positive effect on the therapeutic response. Finally, we describe some interesting recent discoveries of novel treatments related to the antioxidant system for pancreatic cancer, including natural or synthetic compounds with therapeutic properties

Phytochemical Combinations Modulate the Activation of Nrf2 and Expression of SOD<em> </em>in Pancreatic Cancer Cells More Efficiently Than Single Plant Components

Pancreatic adenocarcinoma mainly occurs in elderly people. Thus, the management of pancreatic cancer in the aging population is becoming increasingly relevant. In this preliminary study we evaluated the effect of selected phytochemicals and their combinations on the expression and activation of Nrf2 transcription factor in the human pancreatic cancer cell line MIA-Pa-Ca-2. Treatment for 24 h with xanthohumol (X), resveratrol (RES), indole-3-carbinol (I3C) or phenethyl isothiocyanate (PEITC) had no effect on the expression and activation of Nrf2, or the expression of the SOD gene controlled by Nrf2. However, combinations of these phytochemicals significantly increased Nrf2 activation and subsequently the expression of SOD. The most efficient were the mixtures of resveratrol and glucosinolates degradation products, I3C and PEITC. These results indicate that combinations of phytochemicals resembling that occurring in natural diets may efficiently modulate the signaling pathways, whose proper function is important for pancreatic cancer prophylaxis or improving the results of conventional therapy

THE COMPARISON OF THE EFFECTS OF PANOBINOSTAT AND PKF118-310 ON β-CATENIN-DEPENDENT TRANSCRIPTION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA CELL LINES

Advanced head and neck squamous cell cancers (HNSCC) have unfavorable prognosis and new therapeutic options are necessary to improve treatment outcomes. The Wnt pathway plays an important role in the pathogenesis and progression of HNSCC. The aim of this study was to assess the effects of a histone deacetylase inhibitor – panobinostat on Wnt-dependent gene expression and on cell migration. Cell viability in HNSCC cell lines (BICR6, CAL27, FaDu, H314, SCC-25) was evaluated by MTT assay. The expression of β-catenin-target genes was assessed by qPCR and TCF/LEF-dependent reporter assay. Protein content was evaluated by Western blot. Cell migration was analyzed by the wound healing assay. Panobinostat showed differential modulation of gene expression. It reduced the level of Axin2 in CAL27 and SCC-25 cells but upregulated its expression in BICR6 and H314 cell lines. Moreover, it diminished the expression of MMP7 in BICR6, H314 and CAL27 cell lines. In contrast, the inhibitor of β-catenin transcriptional activity – PKF118-310 down-regulated the expression of β-catenin-target genes in HNSCC cell lines. Interestingly, panobinostat had opposite effects on cell migration in CAL27 and FaDu where it inhibited or stimulated migration, respectively. On the other hand, PKF118-310 reduced cell migration. The anti-cancer effects of panobinostat in HNSCC cells are rather not related to the inhibition of Wnt signaling. PKF118-310 attenuates Wnt signaling, but only in a limited number of HNSCC cell lines. Importantly, the inhibition of Wnt pathway reduces the capacity of cells for migration suggesting that it may potentially therapeutically reduce cell invasion