• NF‐κB inhibitors
• anti‐inflammatory activity
• mollugin derivatives

• Animals
• NF-kappa B/metabolism
• NF-kappa B/antagonists & inhibitors
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/chemical synthesis
• Mice
• Drug Design
• Molecular Docking Simulation
• Quassins/pharmacology
• Quassins/chemistry
• Quassins/chemical synthesis
• Lipopolysaccharides/pharmacology
• Lipopolysaccharides/antagonists & inhibitors
• Signal Transduction/drug effects
• RAW 264.7 Cells
• Structure-Activity Relationship
• Male
• Humans
• Inflammation/drug therapy
• Inflammation/metabolism

• National Natural Science Foundation of China

Magnolol is a natural compound extracted from Chinese herbal medicine and can induce apoptosis in numerous types of cancer cells. However, the molecular mechanisms of magnolol in oral cancer are still unclear. In this study, we investigated the anti-cancer effects and underlying mechanisms of magnolol in human oral cancer cell lines. Our results exhibited that magnolol inhibited the cell proliferation via inducing the sub-G1 phase and cell apoptosis of HSC-3 and SCC-9 cells. The human apoptosis array and Western blot assay showed that magnolol increased the expression of cleaved caspase-3 proteins and heme oxygenase-1 (HO-1). Moreover, we proved that magnolol induces apoptosis in oral cancer cell lines via the c-Jun N-terminal kinase (JNK)1/2 and p38 pathways. Overall, the current study supports the role for magnolol as a therapeutic approach for oral cancer through JNK1/2- and p38-mediated caspase activation.

• JNK1/2
• apoptosis
• magnolol
• oral cancer
• p38

• Apoptosis
• Calcium Channels/metabolism
• Carcinoma, Squamous Cell/metabolism
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Potential, Mitochondrial
• Mitochondrial Membrane Transport Proteins
• Mouth Neoplasms/metabolism
• NF-E2-Related Factor 2/metabolism
• Phenotype
• Spermine/pharmacology
• Squamous Cell Carcinoma of Head and Neck/metabolism

• zoopharmacology, zoopharmacognosy, zootherapy, cancer, multidrug resistance (MDR), collateral sensitivity, oncotherapy

• Animals
• Antineoplastic Agents/pharmacology
• Drug Discovery
• Drug Resistance, Neoplasm/drug effects
• Neoplasms/drug therapy

• UID/DTP/04567/2020 Fundação para a Ciência e a Tecnologia

Interactions of the receptor for advanced glycation end product (RAGE) and its ligands in the context of their role in diabetes mellitus, inflammation, and carcinogenesis have been extensively investigated. This review focuses on the role of RAGE-ligands and anti-RAGE drugs capable of controlling cancer progression. Different studies have demonstrated interaction of RAGE with a diverse range of acidic (negatively charged) ligands such as advanced glycation end products (AGEs), high-mobility group box1 (HMGB1), and S100s, and their importance to cancer progression. Some RAGE-ligands displayed effects on anti- and pro-apoptotic proteins through upregulation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) pathways, while downregulating p53 in cancer progression. In addition, RAGE may undergo ligand-driven multimodal dimerization or oligomerization mediated through self-association of some of its subunits. We conclude our review by proposing possible future lines of study that could result in control of cancer progression through RAGE inhibition.

• AGEs
• HMGB1
• RAGE-inhibitors
• RAGE-ligands
• S100s
• carcinogenesis

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Glycation End Products, Advanced/antagonists & inhibitors
• Glycation End Products, Advanced/metabolism
• HMGB1 Protein/antagonists & inhibitors
• HMGB1 Protein/metabolism
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• S100 Proteins/antagonists & inhibitors
• S100 Proteins/metabolism
• Signal Transduction

• Nrf2
• Personalized nutrition
• flavonoid
• goiter
• hyperthyroidism
• hypothyroidism
• phytochemical
• thyroid.

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.

• LPS
• Nrf2
• gastrodin
• lung injury

• Rubia cordifolia L.
• UPLC/Q-TOF-MS
• alizarin
• metabolites
• purpurin

• Administration, Oral
• Animals
• Anthraquinones/blood
• Anthraquinones/chemistry
• Anthraquinones/urine
• Chromatography, High Pressure Liquid
• Glucuronides/blood
• Glucuronides/chemistry
• Glucuronides/urine
• Male
• Plant Extracts/chemistry
• Plant Extracts/metabolism
• Rats, Sprague-Dawley
• Rubia/chemistry
• Tandem Mass Spectrometry

The NF-κB signaling pathway plays a pivotal role in regulating the immune response and inflammation. However, it has been shown that NF-κB also has a major role in oncogenesis. Therefore, NF-κB inhibitors have been considered as potential drugs against cancer. Herein, we searched for NF-κB inhibitors from natural sources and identified mollugin from the roots of Rubia cordifolia L. as an inhibitor of NF-κB activation. We found that mollugin significantly inhibited the expression of an NF-κB reporter gene induced by tumor necrosis factor (TNF)-α in a dose-dependent manner. Moreover, mollugin inhibited TNF-α-induced phosphorylation and nuclear translocation of p65, phosphorylation and degradation of inhibitor of κB (IκBα), and IκB kinase (IKK) phosphorylation. Furthermore, we discovered that pretreatment of cells with mollugin prevented the TNF-α-induced expression of NF-κB target genes, such as genes related to proliferation (COX-2, Cyclin D1 and c-Myc), anti-apoptosis (Bcl-2, cIAP-1 and survivin), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). We also demonstrated that mollugin potentiated TNF-α-induced apoptosis and inhibited proliferation of HeLa cells. We further demonstrated in vivo that mollugin suppressed the growth of tumor xenografts derived from HeLa cells. Taken together, mollugin may be a valuable candidate for cancer treatment by targeting NF-κB.

• NF-κB
• NF-κB target genes
• cancer
• mollugin

• Animals
• Apoptosis/drug effects
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• HeLa Cells
• Humans
• I-kappa B Proteins/genetics
• Mice
• NF-KappaB Inhibitor alpha/genetics
• NF-kappa B/genetics
• Neoplasm Proteins/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Pyrans/administration & dosage
• Pyrans/chemistry
• Transcription Factor RelA/genetics
• Tumor Necrosis Factor-alpha/genetics
• Xenograft Model Antitumor Assays

• advanced glycation end products
• apoptosis regulator Bcl-x
• extracellular signal-regulated kinase
• nuclear factor-erythroid 2-related factor 2
• phosphorylation
• tumor protein p53

• Rubiae Radix et Rhizoma
• botany
• pharmacology
• phytochemistry
• review
• toxicology

• Animals
• China
• Drugs, Chinese Herbal/pharmacology
• Humans
• Mice
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Plant Extracts/toxicity
• Plant Roots/chemistry
• Plants, Medicinal/chemistry
• Rats
• Rhizome/chemistry
• Rubia/chemistry

• Rubia cordifolia L.
• UHPLC-MS/MS
• mollugin
• munjistin
• pharmacokinetics
• purpurin

• Administration, Oral
• Animals
• Anthraquinones/chemistry
• Anthraquinones/pharmacokinetics
• Chromatography, High Pressure Liquid
• Drug Stability
• Drugs, Chinese Herbal/administration & dosage
• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/pharmacokinetics
• Male
• Molecular Structure
• Plant Extracts/administration & dosage
• Plant Extracts/chemistry
• Plant Extracts/pharmacokinetics
• Pyrans/chemistry
• Pyrans/pharmacokinetics
• Rats
• Reproducibility of Results
• Rubia/chemistry
• Sensitivity and Specificity
• Tandem Mass Spectrometry

Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype.

While the mechanisms underlying KSHV induction of HO-1 remain unknown, the cellular mechanisms that regulate HO-1 expression have been extensively investigated in the context of basal and pathophysiological states. The detoxifying action of HO-1 is critical for the protection of cells exposed to high heme levels. KS spindle cells are erythrophagocytic and contain erythrocyte ghosts. Erythrocyte degeneration leads to the localized release of heme, creating oxidative stress that may be further exacerbated by environmental or other cofactors. Our previous work showed that KSHV-infected cells proliferate in response to heme and that this occurs in a HO-1-dependent manner. We therefore hypothesize that KSHV induction of HO-1 contributes to KS tumor development via heme metabolism and propose that HO-1 be evaluated as a therapeutic target for KS. Our present work, which aimed to understand the mechanisms whereby KSHV induces HO-1, will be important for the design and implementation of such a strategy.

AIM: To investigate the effect of zinc protoporphyrin IX on the response of hepatoma cells to cisplatin and the possible mechanism involved.

METHODS: Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by a flow cytometric assay. Western blotting was used to measure protein expression. Heme oxygenase (HO)-1 activity was measured by determining the level of bilirubin generated in isolated microsomes. Reactive oxygen species (ROS) production was monitored by flow cytometry. Caspase-3 activity was measured with a colorimetric assay kit. Mice were inoculated with 1 × 10⁷ tumor cells subcutaneously into the right flanks. All mice were sacrificed 6 wk after the first treatment and tumors were weighed and measured.

RESULTS: Overexpression of HO-1 in HepG2 cell line was associated with increased chemoresistance to cis-diaminedichloroplatinum (cisplatin; CDDP) compared to other cell lines in vitro. Inhibition of HO-1 expression or activity by zinc protoporphyrin IX (ZnPP IX) markedly augmented CDDP-mediated cytotoxicity towards all liver cancer cell lines in vitro and in vivo. In contrast, induction of HO-1 with hemin increased resistance of tumor cells to CDDP-mediated cytotoxicity in vitro and in vivo. Furthermore, cells treated with ZnPP IX plus CDDP exhibited marked production of intracellular ROS and caspase-3 activity, which paralleled the incidence of cell apoptosis, whereas hemin decreased cellular ROS and caspase-3 activity induced by CDDP.

CONCLUSION: ZnPP IX increases cellular sensitivity and susceptibility of liver cancer cell lines to CDDP and this may represent a mechanism of increasing ROS.

• Zinc protoporphyrin IX
• Heme oxygenase-1
• Liver cancer cell lines
• Cisplatin
• Chemotherapy

• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Caspase 3/metabolism
• Cisplatin/administration & dosage
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Heme Oxygenase-1/metabolism
• Hemin/pharmacology
• Hep G2 Cells
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mice, Nude
• Oxidative Stress/drug effects
• Protoporphyrins/administration & dosage
• Reactive Oxygen Species/metabolism
• Time Factors
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays

Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl₂), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.