NF‐κB is a transcription factor that induces inflammatory cytokines and anti‐apoptotic proteins. NF‐κB is often constitutively activated in human cancers and leukemias, which might increase the ...malignant character of neoplastic diseases. Therefore, NF‐κB inhibitors might be useful as anticancer agents. Our research team designed a new NF‐κB inhibitor that is based on the structure of the antibiotic epoxyquomicin C isolated from a microorganism. The designed compound, DHMEQ, inhibited the ligand‐induced activation of NF‐κB, and it also inhibited the constitutively activated NF‐κB in cancer cells. DHMEQ is a unique inhibitor of NF‐κB that acts at the level of the nuclear translocation. It inhibited both canonical and non‐canonical NF‐κB activating pathways. It inhibited various carcinomas and leukemias in animal models without any toxicity, and might be useful as an anticancer agent. (Cancer Sci 2006; 97: 990–995)
Not only physiological phenomena but also pathological phenomena can now be explained by the change of signal transduction in the cells of specific tissues. Commonly used cellular signal ...transductions are limited. They consist of the protein-tyrosine kinase dependent or independent Ras-ERK pathway, and the PI3K-Akt, JAK-STAT, SMAD, and NF-κB-activation pathways. In addition, biodegradation systems, such as the ubiquitin-proteasome pathway and autophagy, are also important for physiological and pathological conditions. If we can control signaling for each by a low-molecular-weight agent, it would be possible to treat diseases in new ways. At present, such cell signaling inhibitors are mainly looked for in plants, soil microorganisms, and the chemical library. The screening of bioactive metabolites from deep-sea organisms should be valuable because of the high incidence of finding novel compounds. Although it is still an emerging field, there are many successful examples, with new cell signaling inhibitors. In this review, we would like to explain the current view of the cell signaling systems important in diseases, and show the inhibitors found from deep-sea organisms, with their structures and biological activities. These inhibitors are possible candidates for anti-inflammatory agents, modulators of metabolic syndromes, antimicrobial agents, and anticancer agents.
In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract ...of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer's disease, amyloid-β-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer's model using flies. Learning deficits were induced by the overexpression of amyloid-β42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.
Macroautophagy is a cellular response that leads to the bulk, nonspecific degradation of cytosolic components, including organelles. In recent years, it has been recognized that autophagy is ...essential for prevention of neurodegenerative diseases, including Parkinson disease (PD) and Huntington disease (HD). Here, we show that conophylline (CNP), a vinca alkaloid, induces autophagy in an mammalian target of rapamycin-independent manner. Using a cellular model of PD, CNP suppressed protein aggregation and protected cells from cell death caused by treatment with 1-methyl-4-phenylpyridinium, a neurotoxin, by inducing autophagy. Moreover, in the HD model, CNP also eliminated mutant huntingtin aggregates. Our findings demonstrate the possible use of CNP as a therapeutic drug for neurodegenerative disorders, including PD and HD.
Background: Autophagy is essential for prevention of neurodegenerative diseases.
Results: Conophylline induces mTOR-independent autophagy and protects against neurotoxicity.
Conclusion: Conophylline protects cells by enhancement of autophagy in models of neurodegenerative diseases.
Significance: Conophylline would be a therapeutic agent for neurodegenerative diseases.
Endometriosis, a common gynecological disorder characterized by the growth of endometrial gland and stroma outside the uterus, causes several symptoms such as dysmenorrhea, hypermenorrhea, and ...chronic abdominal pain. 17β estradiol (E2) stimulates the growth of endometriotic lesions. Although estetrol (E4), produced by human fetal liver, is also a natural estrogen, it may have the opposite effects on endometriotic cells. We investigated different effects of E4 and E2 on the invasion and migration of immortalized human endometrial stromal cells (HESCs) and evaluated whether E4 affects the expression of Wiskott-Aldrich syndrome protein (WASP) family member 1 (WASF-1). We measured the invasion of HESCs by a Matrigel chamber assay. Cell migration was measured by wound healing assay and cell tracking analysis. The expression of WASF-1 was confirmed by independent real-time PCR analysis. Transfection of cells with siRNAs was carried out to knock down the expression of WASF-1 in HESCs. E4 significantly inhibited E2-induced invasion and migration of HESCs. WASF-1 was found to be a potential mediator based on metastasis PCR array. WASF-1 was upregulated by E2 and downregulated by E4. Knockdown of WASF-1 inhibited migration. Our results suggest that E4 may inhibit E2-induced growth of endometriotic lesions. Downregulation of WASF-1 is involved in the inhibitory effects of E4 on migration. The use of E4 combined with progestins as combined oral contraceptives may cause endometriotic lesions to regress in women with endometriosis.
We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed ...anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.
Safe and effective nonsteroidal anti-inflammatory drugs are needed. Meanwhile, addition of amino acids to cultures of microorganisms is likely to increase the possibility of novel secondary ...metabolite isolation. In the course of screening for anti-inflammatory agents using cellular lipopolysaccharide (LPS)-induced nitric oxide (NO) production, two new related compounds with the myceliothermophin structure from a methionine-enriched culture of Myceliophthora thermophila ATCC 42464 were isolated. The new compounds have an additional methylthio group on the myceliothermophin structure and were named myceliostatins A and B. Both compounds inhibited LPS-induced NO production at nontoxic concentrations in macrophage-like mouse monocytic leukemia RAW264.7 cells. Myceliostatin B inhibited the expression of LPS-induced iNOS, IL-6, and IL-1β and the upstream NF-κB activity in situ and in vitro. Finally, it was found to inhibit NF-κB binding to DNA in the reconstruction system with purified p65. Myceliostatin B also inhibited LPS-induced reactive oxygen species (ROS) production. Thus, myceliostatin B, a novel compound derived from M. thermophila, was found to be a new anti-inflammatory and antioxidant compound directly inhibiting NF-κB.
Background and Aims
Chronic HBV infection is a major health problem worldwide. Currently, the first‐line treatment for HBV is nucleos(t)ide analogs or interferons; however, efficient therapeutic ...approaches that enable cure are lacking. Therefore, anti‐HBV agents with mechanisms distinct from those of current drugs are needed. Sodium taurocholate cotransporting polypeptide (NTCP) was previously identified as an HBV receptor that is inhibited by several compounds. Farnesoid X receptor (FXR) activation also inhibits NTCP function.
Approach and Results
In this study, we investigated the inhibitory effect of bile acid (BA) derivatives—namely obeticholic acid (OCA), 6α‐ethyl‐24‐nor‐5β‐cholane‐3α,7α,23‐triol‐23 sulfate sodium salt (INT‐767; a dual agonist of FXR and Takeda G protein‐coupled receptor TGR5), and 6α‐ethyl‐23(S)‐methyl‐cholic acid (INT‐777; a TGR5 agonist)—3‐(2,6‐dichlorophenyl)‐4‐(3′‐carboxy‐2‐chlorostilben‐4‐yl)oxymethyl‐5‐isopropylisoxazole (GW4064; a FXR agonist), cyclosporin A, and irbesartan. OCA and INT‐777 suppressed HBV infection in HepG2‐human NTCP‐C4 cells. Interestingly, INT‐767 showed potent inhibition by attaching to HBV particles rather than binding to NTCP. As an entry inhibitor, INT‐767 was stronger than various natural BAs. Furthermore, in chimeric mice with humanized liver, INT‐767 markedly delayed the initial rise of HBsAg, HBeAg, and HBV DNA and reduced covalently closed circular DNA. The strong inhibitory effect of INT‐767 may be due to the cumulative effect of its ability to inhibit the entry of HBV and to stimulate FXR downstream signaling, which affects the postentry step.
Conclusions
Our results suggest that BA derivatives, particularly INT‐767, are prospective candidate anti‐HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of anti‐HBV agents.
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. ...Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF.
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