Antitumor activity of nanoemulsion based on essential oil of Pinus koraiensis pinecones in MGC-803 tumor-bearing nude mice

Essential oil is the natural extract rich in terpenoids, showing various physiological activities. Our previous studies have proved that essential oil of Pinus koraiensis pinecones (PEO) can inhibit the proliferation of MGC-803 cells and promote cell apoptosis in vitro via the HIPPO/YAP signaling pathway. In this study, we prepared the PEO nanoemulsion and studied its physicochemical properties and anti-tumor activity in MGC-803 tumor-bearing nude mice. The PEO nanoemulsion showed good stability, with an average particle size of 46.87 nm, a zeta potential of 34.4 mV, and a polydispersity index (PDI) of 0.121. The results of anti-tumor experiments showed that the PEO nanoemulsion can effectively inhibit the growth of tumor and promote the apoptosis. In addition, immunohistochemical results showed that the PEO nanoemulsion could inhibit the proliferation of MGC-803 cells by down-regulating the expression of YAP1/TEAD and its target proteins CTGF, AREG and GLI2 to regulate the HIPPO/YAP signaling pathway and its downstream signaling pathway. This study could provide the theoretical basis for the application of essential oils.     

Zinc oxide nanoparticles promotes ferroptosis to repress cancer cell survival and inhibits invasion and migration by targeting miR-27a-3p/YAP axis in renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a prevalent malignancy with growing mortality and high metastasis. Ferroptosis has been identified as an essential process in cancer development, but the regulatory mechanism underlying the RCC progression remains obscure. The nanomaterial zinc oxide nanoparticles (ZONs) have presented anti-cancer function. Here, we identified the critical role of ZONs in promoting ferroptosis of RCC cells by regulating miR-27a-3p/YAP axis.MethodsThe effect of ZONs on RCC was analyzed by qPCR, Western blot, MTT assays, colony formation assays, Flow cytometry analysis, transwell assays, wound healing assays, iron assays, lipid ROS detection, luciferase reporter gene assays, and tumor xenograft.ResultsThe treatment of ZONs repressed expression of GPX4 and SLC7A11 and enhanced ROS accumulation and iron/Fe²⁺ levels in RCC cells. Ferroptosis activator erastin repressed RCC cell viabilities and ZONs further repressed this effect. ZONs inhibited invasion and migration of RCC cells and treatment of ZONs represses RCC cell survival in vitro. ZONs suppressed RCC cell growth in tumorigenicity mouse model. Mechanically, ZONs down-regulated YAP expression by inducing miR-27a-3p, in which YAP overexpression and miR-27a-3p inhibition reverse ZONs -inhibited RCC cell survival in vitro.DiscussionThus, we concluded that ZONs induced RCC cell ferroptosis to suppress RCC cell survival by targeting miR-27a-3p/YAP axis. The clinical significance of ZONs for the treatment of RCC is required to further study and may benefit the targeted therapy of RCC.     

Suppressed Migration and Enhanced Cisplatin Chemosensitivity in Human Cancer Cell Lines by Tuning the Molecular Mobility of Supramolecular Biomaterials

Cancer cells recognize physical cues transmitted from the surrounding microenvironment, and accordingly alter the migration and chemosensitivity. Cell adhesive biomaterials with tunable physical properties can contribute to the understanding of cancer cell responses, and development of new cancer therapies. Previously, it was reported that polyrotaxane-based surfaces with molecular mobility effectively modulate cellular functions via the yes-associated protein (YAP)-related signaling pathway. In the present study, the impact of molecular mobility of polyrotaxane surfaces on the migration and chemosensitivity of lung (A549), pancreatic (BxPC-3), and breast cancer (MDA-MB-231) cell lines is investigated, and it is found that the cellular spreading of adherent A549 and BxPC-3 cells and nuclear YAP translocation are promoted on low-mobility surfaces, suggesting that cancer cells alter their subcellular YAP localization in response to molecular mobility. Furthermore, low-mobility surfaces suppress cellular migration more than high-mobility surfaces. Additionally, low-mobility surfaces promote the cisplatin chemosensitivity of each cancer cell line to a greater extent than high-mobility surfaces. These results suggest that the molecular mobility of polyrotaxane surfaces suppresses cellular migration and enhances chemosensitivity via the subcellular translocation of YAP in cancer cells. Biointerfaces based on polyrotaxanes can thus be a new platform for elucidating cancer cell migration and chemoresistance mechanisms.     

Crosstalk events in the estrogen signaling pathway may affect tamoxifen efficacy in breast cancer molecular subtypes

Steroid hormones are involved on cell growth, development and differentiation. Such effects are often mediated by steroid receptors. One paradigmatic example of this coupling is the estrogen signaling pathway. Its dysregulation is involved in most tumors of the mammary gland. It is thus an important pharmacological target in breast cancer. This pathway, however, crosstalks with several other molecular pathways, a fact that may have consequences for the effectiveness of hormone modulating drug therapies, such as tamoxifen. For this work, we performed a systematic analysis of the major routes involved in crosstalk phenomena with the estrogen pathway – based on gene expression experiments (819 samples) and pathway analysis (493 samples) – for biopsy-captured tissue and contrasted in two independent datasets with in vivo and in vitro pharmacological stimulation. Our results confirm the presence of a number of crosstalk events across the estrogen signaling pathway with others that are dysregulated in different molecular subtypes of breast cancer. These may be involved in proliferation, invasiveness and apoptosis-evasion in patients. The results presented may open the way to new designs of adjuvant and neoadjuvant therapies for breast cancer treatment.     

AMP kinase/cyclooxygenase-2 pathway regulates proliferation and apoptosis of cancer cells treated with quercetin

AMPK (AMP-activated protein kinase) is highly conserved in eukaryotes, where it functions primarily as a sensor of cellular energy status. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumor cells. In this study, quercetin activated AMPK in MCF breast cancer cell lines and HT-29 colon cancer cells, and this activation of AMPK seemed to be closely related to a decrease in COX-2 expression. The application of a COX-2 inhibitor or cox-2^-/- cells supported the idea that AMPK is an upstream signal of COX-2, and is required for the anti-proliferatory and pro-apoptotic effects of quercetin. The suppressive or growth inhibitory effects of quercetin on COX-2 were abolished by treating cancer cells with an AMPK inhibitor Compound C. These results suggest that AMPK is crucial to the anti-cancer effect of quercetin and that the AMPK-COX-2 signaling pathway is important in quercetin-mediated cancer control.     

Metal-Free Reductive Coupling of para-Quinone Methides with 4-Cyanopyridines Enabled by Pyridine-Boryl Radicals: Access to Pyridylated Diarylmethanes with Anti-Cancer Activity

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B₂pin₂) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.     

Identification of key genes of hesperidin in inhibition of breast cancer stem cells by functional network analysis

Breast cancer therapy with classical chemotherapy is unable to eradicate breast cancer stem cells (BCSCs). Loss of p53 function causes growth and differentiation in cancer stem cells (CSCs); therefore, p53-targeted compounds can be developed for BCSCs-targeted drugs. Previously, hesperidin (HES), a citrus flavonoid, showed anticancer activities and increased efficacy of chemotherapy in several types of cancer in vitro and in vivo. This study was aimed to explore the key protein and molecular mechanism of hesperidin in the inhibition of BCSCs using bioinformatics and in vitro study. Bioinformatics analysis revealed about 75 potential therapeutic target proteins of HES in BCSCs (TH), in which TP53 was the only direct target protein (DTP) with a high degree score. Furthermore, the results of GO enrichment analysis showed that TH was taken part in the biological process of regulation of apoptosis and cell cycle. The KEGG pathway enrichment analysis also showed that TH is involved in several pathways, including cell cycle, p53 signaling pathway. In vitro experiment results showed that HES inhibited cell proliferation, mammosphere, and a colony formation, and migration in on MCF-7 3D cells (mammospheres). HES induced G0/G1 cell cycle arrest and apoptosis in MCF-7 cells 3D. In addition, HES treatment reduced the mRNA level of p21 but increased the mRNA level of cyclin D1 and p53 in the mammosphere. HES inhibits BCSCs in mammospheres. More importantly, this study highlighted p53 as a key protein in inhibition of BCSCs by HES. Future studies on the molecular mechanism are needed to validate the results of this study.     

Inhibitors of tyrosine kinase proteins induced Ras signaling pathway as potential anti-tumor agents

Cellular signaling pathways induced by growth-factor receptors with tyrosine kinase activity are frequently deregulated in cancer. Anti-tumor agents that inhibit their enzymatic tyrosine kinase activity have been designed and are now used in human chemotherapy. We review here our data constituting an alternative way to interrupt over-expressed signaling pathway by inhibiting protein-protein interactions. In our approach, the adaptor protein Grb2 over-expressed in connection with HER2/ErbB2/neu in Ras signaling pathway was chosen as a target. Peptides and peptidomimetics with very high affinities for either SH3 or SH2 domains of Grb2 were rationally designed from structural data. We describe their synthesis, their capacity to interrupt the signaling pathway and their anti-proliferative activity. To cite this article: M. Vidal et al., C. R. Chimie 8 (2005).     

Effects of HPV Status on Responsiveness to Ionizing Radiation vs Photodynamic Therapy in Head and Neck Cancer Cell lines

Efficacy of ionizing radiation (I/R) was compared with phototoxic effects of photodynamic therapy (PDT) in vitro using two cell lines derived from patients with head and neck squamous cell carcinoma (HNSCC). A cell line derived from a donor with a human papilloma virus (HPV) infection was more responsive to I/R but significantly less responsive to PDT than a cell line derived from an HPV-free patient. Cell death after I/R in the HPV(+) cell line was associated with increased DEVDase activity, a hallmark of apoptosis. The HPV(−) line was considerably less responsive to I/R, with DEVDase activity greatly reduced, suggesting an impaired apoptotic program. In contrast, the HPV(−) cells were readily killed by PDT when the ER was among the targets for photodamage. While DEVDase activity was enhanced, the death pathway appears to involve paraptosis until the degree of photodamage reached the LD₉₉ range. These data suggest that PDT-induced paraptosis can be a death pathway for cells with an impaired apoptotic program.     

Piperine loaded zinc oxide nanocomposite inhibits the PI3K/AKT/mTOR signaling pathway via attenuating the development of gastric carcinoma: In vitro and in vivo studies

Gastric cancer (GC) is the fifth most cancer type and the third most cause of cancer-associated deaths worldwide along with the 5-year survival rate is less the 30%. This investigation was aimed to synthesis the piperine-loaded zinc oxide nanocomposite (ZnO-Pip-NC) and investigating its anticancer activity against the GC by in vitro and in vivo models by the inhibiting the apoptotic and PI3K/Akt/mTOR signaling pathways. The synthesized ZnO-Pip-NC was characterized by different techniques. The cytotoxicity of zinc oxide, piperine and the formulated ZnO-Pip-NC was tested against the AGS cells by MTT assay. The intracellular ROS level, mitochondrial membrane potential, and apoptotic cell necrosis in the AGS cells was examined by fluorescent staining techniques. The expression of apoptotic and PI3K/Akt/mTOR signaling markers were inspected by western blotting and the expression of pro0inflammatory markers analyzed by RT-PCR technique. The antioxidant levels were examined by standard methods and histopathology of gastric mucosa was analyzed. The ZnO-Pip-NC treatment appreciably inhibited the AGS cell viability. ZnO-Pip-NC treated cells also exhibited excessive intracellular ROS, diminished MMP, nuclear damages, and apoptosis induction in AGS cells. The enhanced expression of pro-apoptotic proteins and inhibition of PI3K/Akt/mTOR signaling pathway was noted in ZnO-Pip-NC treated cells. In vivo studies proved that the ZnO-Pip-NC noticeably restored the antioxidants in the GC animals and also prevented the gastric mucosa and inhibited the GC tumor formation. In conclusion, the findings of this investigation confirmed the anticancer potential of ZnO-Pip-NC against the GC via inhibiting the PI3K/Akt/mTOR signaling pathway.     

Volatile organic compounds in head and neck squamous cell carcinoma—An in vitro pilot study

Owing to the lack of specific symptoms, diagnosis of head and neck squamous cell carcinoma (HNSCC) may be delayed. We evaluated volatile organic compounds in tumor samples from patients suffering from HNSCC and tested the hypothesis that there is a characteristic altered composition in the headspace of HNSCC compared with control samples from the same patient with normal squamous epithelium. These results provide the basis for future noninvasive breath analysis in HNSCC. Headspace air of suspected tumor and contralateral control samples in 20 patients were analyzed using ion-mobility spectrometry. Squamous cell carcinoma was diagnosed in 16 patients. In total, we observed 93 different signals in headspace measurements. Squamous cell carcinomas revealed significantly higher levels of volatile cyclohexanol (0.54 ppb_v, 25th to 75th percentiles 0.35–0.86) compared with healthy squamous epithelium (0.24 ppb_v, 25th to 75th percentiles 0.12–0.3; p < 0.001). In conclusion, head and neck squamous cell carcinoma emitted significantly higher levels of volatile cyclohexanol in headspace compared with normal squamous epithelium. These findings form the basis for future breath analysis for diagnosis, therapy control and the follow-up of HNSSC to improve therapy and aftercare.     

Libertellenone H,a Natural Pimarane Diterpenoid,Inhibits Thioredoxin System and Induces ROS-Mediated Apoptosis in Human Pancreatic Cancer Cells

Libertellenone H (LH), a marine-derived pimarane diterpenoid isolated from arctic fungus Eutypella sp. D-1, has shown effective cytotoxicity on a range of cancer cells. The present study is to explore the anticancer effect of LH on human pancreatic cancer cells and to investigate the intracellular molecular target and underlying mechanism. As shown, LH exhibited anticancer activity in human pancreatic cancer cells by promoting cell apoptosis. Mechanistic studies suggested that LH-induced reactive oxygen species (ROS) accumulation was responsible for apoptosis as antioxidant N-acetylcysteine (NAC) and antioxidant enzyme superoxide dismutase (SOD) antagonized the inhibitory effect of LH. Zymologic testing demonstrated that LH inhibited Trx system but had little effect on the glutathione reductase and glutaredoxin. Mass spectrometry (MS) analysis revealed that the mechanism of action was based on the direct conjugation of LH to the Cys³²/Cys³⁵ residue of Trx1 and Sec⁴⁹⁸ of TrxR, leading to a decrease in the cellular level of glutathione (GSH) and activation of downstream ASK1/JNK signaling pathway. Taken together, our findings revealed LH was a marine derived inhibitor of Trx system and an anticancer candidate.     

Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol

Rab coupling protein (RCP) is upregulated in head and neck squamous cell carcinoma (HNSCC) and is correlated with the progression and survival of patients. However, the role of RCP in one of the aggressive types of HNSCC, oral squamous cell carcinoma (OSCC), remains elusive. In the present study, we identified the important role of Zeb1 in RCP-induced OSCC epithelial-to-mesenchymal transition (EMT) and invasion. RCP induces Zeb1 expression, and silencing Zeb1 expression significantly inhibits RCP-induced OSCC invasion. In addition, Zeb1 upregulates MT1-MMP expression to promote OSCC EMT and invasion. Furthermore, we observed that the β1 integrin/EGFR/β-catenin signaling cascade mediates RCP-induced Zeb1 expression to promote OSCC invasion. Notably, we provide evidence that resveratrol (REV) strongly inhibits RCP-induced Zeb1 expression through blocking β1 integrin endosome recycling and EGFR activation, leading to suppression of RCP-induced OSCC invasion, demonstrating the important role of RCP in OSCC invasion and its reversion by REV. Collectively, the present study provides evidence for the first time that RCP aggravates OSCC invasion through increasing Zeb1 expression and subsequently upregulating MT1-MMP expression and that this process is reversed by REV, providing novel biomarkers and indicating the therapeutic potential of REV in OSCC.Subject terms: Oral cancer, Cell invasion     

Averrhoa carambola extractive inhibits breast cancer via regulating CEPT1 and LYPLA1

Liposomes have been widely exploited as a drug delivery system in treating tumors because of their advantage to enhance anti-tumor efficacy and reduce side effects. In this study, the tumor-targeted 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4?dione (DMDD, i.e., Averrhoa carambola extractive) liposomes (HA/TN-DLP) were conducted and assessed. HA/TN-DLP showed controllable drug loading (up to 83%) with high stability. In vitro and in vivo studies showed good cell uptake behavior and high inhibition rate of breast cancer compared to free DMDD. HA/TN-DLP might be the suitable for DMDD due to its better advantages in delivery, penetrability, and targeting-tumor capability. For in vivo mouse model tests, HA/TN-DLP effectively inhibited tumor growth compared to free DMDD. Further analyses indicated that HA/TN-DLP inhibited the glycerophospholipid metabolism pathway by reducing the biosynthesis of phosphatidylcholine and 1-acyl-sn?glycero-3-phosphocholine through regulating the expressions of CEPT1 and LYPLA1, and inhibited tumor cell growth by regulating the PI3K/Akt and NF-κB signaling pathways. In conclusion, the obviously enhanced antitumor effect further demonstrated that HA/TN-DLP may be a promising tumor-targeting agent.     

Bioinformatics and Functional Analyses Implicate Potential Roles for EOGT and L-fringe in Pancreatic Cancers

Notch signaling receptors, ligands, and their downstream target genes are dysregulated in pancreatic ductal adenocarcinoma (PDAC), suggesting a role of Notch signaling in pancreatic tumor development and progression. However, dysregulation of Notch signaling by post-translational modification of Notch receptors remains poorly understood. Here, we analyzed the Notch-modifying glycosyltransferase involved in the regulation of the ligand-dependent Notch signaling pathway. Bioinformatic analysis revealed that the expression of epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) and Lunatic fringe (LFNG) positively correlates with a subset of Notch signaling genes in PDAC. The lack of EOGT or LFNG expression inhibited the proliferation and migration of Panc-1 cells, as observed by the inhibition of Notch activation. EOGT expression is significantly increased in the basal subtype, and low expression of both EOGT and LFNG predicts better overall survival in PDAC patients. These results imply potential roles for EOGT- and LFNG-dependent Notch signaling in PDAC.     

A high concentration of genistein down-regulates activin A, Smad3 and other TGF-β pathway genes in human uterine leiomyoma cells

Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ≥ 1.5 fold, P ≤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 µg/ml) in UtLM cells. Downregulation of TGF-β signaling pathway genes, activin A, activin B, Smad3, TGF-β2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-β pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas.