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Molecular Biology of the Cell Jul 1998
Topics: Animals; Biological Transport; Brefeldin A; COS Cells; Endoplasmic Reticulum; Golgi Apparatus; Green Fluorescent Proteins; Intracellular Membranes; Light; Luminescent Proteins; Membrane Glycoproteins; Microscopy, Video; Vesicular stomatitis Indiana virus; Video Recording; Viral Envelope Proteins
PubMed: 9658158
DOI: 10.1091/mbc.9.7.1617 -
Autophagy Sep 2016Two topics that have attracted recent attention in the field of autophagy concern the source of the membrane that is used to form the autophagosome during macroautophagy...
Two topics that have attracted recent attention in the field of autophagy concern the source of the membrane that is used to form the autophagosome during macroautophagy and the role of noncanonical autophagic pathways. The 2 topics may converge when considering the intersection of autophagy with viral infection. We suggest that noncanonical autophagy, which is sensitive to treatment with brefeldin A, may converge with the infectious cycles of certain DNA and RNA viruses that utilize membrane from the ER and cis-Golgi.
Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Beclin-1; Brefeldin A; Cell Membrane; Coronavirus; Coronavirus Infections; Ebolavirus; Endoplasmic Reticulum; Golgi Apparatus; Humans; Microtubule-Associated Proteins; Virus Diseases
PubMed: 27439673
DOI: 10.1080/15548627.2016.1203489 -
Marine Drugs Apr 2018The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated... (Review)
Review
The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing activity of BFA in cancer cells highlights the possibility of further developing this natural product as an anticancer agent. Besides its biological importance, its structural features have also gathered tremendous interest from both medicinal and synthetic chemists. By a medicinal chemistry and total synthesis approach, numerous analogs from BFA have been developed to improve its inferior bioavailability and its antiproliferative ability. In this review, the recent medicinal chemistry efforts in relation to the production of BFA analogs are extensively presented.
Topics: Antineoplastic Agents; Apoptosis; Biological Availability; Brefeldin A; Cell Proliferation; Humans
PubMed: 29670019
DOI: 10.3390/md16040133 -
American Journal of Physiology. Cell... Aug 2021Endothelial hyperpermeability is the hallmark of acute respiratory distress syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in...
Endothelial hyperpermeability is the hallmark of acute respiratory distress syndrome (ARDS). Laborious efforts in the investigation of the molecular pathways involved in the regulation of the vascular barrier shall reveal novel therapeutic targets toward that respiratory disorder. Herein, we investigate in vitro the effects of the α-1,2-mannosidase 1 inhibitor kifunensine (KIF) and brefeldin A (BFA) in the lipopolysaccharides (LPS)-induced endothelial breakdown. Our results suggest that BFA opposes the deteriorating effects of KIF [unfolded protein response (UPR) suppressor] toward the lung microvasculature. Since KIF is a UPR suppressor, and brefeldin A is a UPR inducer, we suggest that a carefully devised UPR manipulation may deliver novel therapeutic avenues in diseases related to endothelial barrier dysfunction (e.g., ARDS and sepsis).
Topics: Alkaloids; Animals; Brefeldin A; Cattle; Endothelial Cells; Endothelium, Vascular; Humans; Lipopolysaccharides; Lung; Microvessels; Permeability; Respiratory Distress Syndrome
PubMed: 34161151
DOI: 10.1152/ajpcell.00142.2021 -
Cell Death & Disease Jul 2021All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress...
All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
Topics: Activating Transcription Factor 4; Brefeldin A; Cell Cycle; Cell Line; Endoplasmic Reticulum Stress; Ferroptosis; Gene Knockdown Techniques; Humans; Neoplasm Proteins; Phosphorylation; Pyrophosphatases; Stress, Physiological; Transcription, Genetic; Tunicamycin
PubMed: 34294679
DOI: 10.1038/s41419-021-04018-7 -
Molecules (Basel, Switzerland) May 2023Brefeldin A has a wide range of anticancer activity against a variety of tumor cells. Its poor pharmacokinetic properties and significant toxicity seriously hinder its...
Brefeldin A has a wide range of anticancer activity against a variety of tumor cells. Its poor pharmacokinetic properties and significant toxicity seriously hinder its further development. In this manuscript, 25 brefeldin A-isothiocyanate derivatives were designed and synthesized. Most derivatives showed good selectivity between HeLa cells and L-02 cells. In particular, exhibited potent antiproliferative activity against HeLa cells (IC = 1.84 μM) with no obvious cytotoxic activity to L-02 (IC > 80 μM). Further cellular mechanism tests indicated that induced HeLa cell cycle arrest at G1 phase. Cell nucleus fragmentation and decreased mitochondrial membrane potential suggested could induce apoptosis in HeLa cells through the mitochondrial-dependent pathway.
Topics: Female; Humans; HeLa Cells; Uterine Cervical Neoplasms; Brefeldin A; Cell Proliferation; Antineoplastic Agents; Apoptosis; Isothiocyanates; Drug Screening Assays, Antitumor; Cell Line, Tumor; Structure-Activity Relationship
PubMed: 37298761
DOI: 10.3390/molecules28114284 -
FEBS Letters Jul 1992A number of recent observations have suggested that the endocytic and biosynthetic pathways may share fundamentally similar transport mechanisms at the molecular level.... (Review)
Review
A number of recent observations have suggested that the endocytic and biosynthetic pathways may share fundamentally similar transport mechanisms at the molecular level. Some of the more striking of these suggestions have come from a comparison of the effects of the macrocyclic lactone brefeldin A (BFA) on endosomes and the Golgi complex. BFA is thought to affect Golgi-specific coat proteins that may be involved in maintaining the structural integrity of the organelle and in regulating membrane transport in the secretory pathway. Many of the effects of BFA on the endocytic system, such as the guanine nucleotide and aluminum fluoride (AlF4-)-regulated induction of microtubule-dependent endosomal tubules, are strikingly reminiscent of the action of the drug on the Golgi complex. Therefore, the similar mechanisms of action of the drug on endosomes suggest that organelles of the endocytic pathway may be associated with similar cytoplasmic coats that could regulate endosome function and integrity.
Topics: Brefeldin A; Cell Membrane; Cyclopentanes; Endocytosis; Organelles
PubMed: 1639200
DOI: 10.1016/0014-5793(92)80908-y -
Marine Drugs Dec 2021Brefeldin A (), a potent cytotoxic natural macrolactone, was produced by the marine fungus sp. (HS-N-29) from the medicinal mangrove . Series of its ester derivatives -...
Brefeldin A (), a potent cytotoxic natural macrolactone, was produced by the marine fungus sp. (HS-N-29) from the medicinal mangrove . Series of its ester derivatives - were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Their cytotoxic activities were evaluated against human chronic myelogenous leukemia K562 cell line in vitro, and the preliminary structure-activity relationships revealed that the hydroxy group played an important role. Moreover, the monoester derivatives exhibited stronger cytotoxic activity than the diester derivatives. Among them, brefeldin A 7--2-chloro-4,5-difluorobenzoate () exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC value of 0.84 µM. Further evaluations indicated that induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. The expression of downstream signaling molecules in the AKT pathway, including mTOR and p70S6K, was also attenuated after -treatment in a dose-dependent manner. Furthermore, molecular modeling of docked into binding site of an ARF1-GDP-GEF complex represented well-tolerance. Taken together, had the potential to be served as an effective antileukemia agent or lead compound for further exploration.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Brefeldin A; Cell Proliferation; Humans; K562 Cells; Penicillium; Structure-Activity Relationship; Wetlands
PubMed: 35049881
DOI: 10.3390/md20010026 -
Molecules (Basel, Switzerland) Apr 2022The estrogen receptor α (ERα) is an important biological target mediating 17β-estradiol driven breast cancer (BC) development. Aiming to develop innovative drugs...
The estrogen receptor α (ERα) is an important biological target mediating 17β-estradiol driven breast cancer (BC) development. Aiming to develop innovative drugs against BC, either wild-type or mutated ligand-ERα complexes were used as source data to build structure-based 3-D pharmacophore and 3-D QSAR models, afterward used as tools for the virtual screening of National Cancer Institute datasets and hit-to-lead optimization. The procedure identified Brefeldin A () as hit, then structurally optimized toward twelve new derivatives whose anticancer activity was confirmed both in vitro and in vivo. Compounds as SERMs showed picomolar to low nanomolar potencies against ERα and were then investigated as antiproliferative agents against BC cell lines, as stimulators of p53 expression, as well as BC cell cycle arrest agents. Most active leads were finally profiled upon administration to female Wistar rats with pre-induced BC, after which , , , , , and represent potential candidates for BC therapy.
Topics: Animals; Breast Neoplasms; Brefeldin A; Estrogen Receptor alpha; Female; Humans; Quantitative Structure-Activity Relationship; Rats; Rats, Wistar
PubMed: 35566172
DOI: 10.3390/molecules27092823 -
PLoS Pathogens Sep 2023The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses...
The cellular protein GBF1, an activator of Arf GTPases (ArfGEF: Arf guanine nucleotide exchange factor), is recruited to the replication organelles of enteroviruses through interaction with the viral protein 3A, and its ArfGEF activity is required for viral replication, however how GBF1-dependent Arf activation supports the infection remains enigmatic. Here, we investigated the development of resistance of poliovirus, a prototype enterovirus, to increasing concentrations of brefeldin A (BFA), an inhibitor of GBF1. High level of resistance required a gradual accumulation of multiple mutations in the viral protein 2C. The 2C mutations conferred BFA resistance even in the context of a 3A mutant previously shown to be defective in the recruitment of GBF1 to replication organelles, and in cells depleted of GBF1, suggesting a GBF1-independent replication mechanism. Still, activated Arfs accumulated on the replication organelles of this mutant even in the presence of BFA, its replication was inhibited by a pan-ArfGEF inhibitor LM11, and the BFA-resistant phenotype was compromised in Arf1-knockout cells. Importantly, the mutations strongly increased the interaction of 2C with the activated form of Arf1. Analysis of other enteroviruses revealed a particularly strong interaction of 2C of human rhinovirus 1A with activated Arf1. Accordingly, the replication of this virus was significantly less sensitive to BFA than that of poliovirus. Thus, our data demonstrate that enterovirus 2Cs may behave like Arf1 effector proteins and that GBF1 but not Arf activation can be dispensable for enterovirus replication. These findings have important implications for the development of host-targeted anti-viral therapeutics.
Topics: Humans; Enterovirus; Monomeric GTP-Binding Proteins; ADP-Ribosylation Factor 1; HeLa Cells; Poliovirus; Viral Proteins; Enterovirus Infections; Antigens, Viral; Brefeldin A; Guanine Nucleotide Exchange Factors
PubMed: 37721955
DOI: 10.1371/journal.ppat.1011673