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Cell Death & Disease Feb 2020Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different...
Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different mechanisms. In this study, we demonstrated that BD inhibited lung cancer cell proliferation. Apoptosis and autophagy were the most important mechanisms involved in BD-induced lung cancer cell death, and complete autophagic flux was observed in A549 and NCI-H292 cells. In addition, BD significantly improved intracellular reactive oxygen species (ROS) levels. BD-mediated cell apoptosis and autophagy were almost inhibited in cells pretreated with N-acetylcysteine (NAC), an ROS scavenger. Furthermore, MAPK signaling pathway activation contributed to BD-induced cell proliferation inhibition and NAC could eliminate p-ERK and p-JNK upregulation. Finally, an in vivo study indicated that BD inhibited the growth of lung cancer xenografts. Overall, BD is a promising candidate for the treatment of lung cancer owing to its multiple mechanisms and low toxicity.
Topics: A549 Cells; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Quassins; Reactive Oxygen Species; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 32071301
DOI: 10.1038/s41419-020-2317-3 -
Journal of Advanced Research Apr 2024Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate designs because of its...
INTRODUCTION
Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported.
OBJECTIVES
To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action.
METHODS
Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting.
RESULTS
Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model.
CONCLUSIONS
These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.
Topics: Animals; Humans; Female; Breast Neoplasms; Signal Transduction; Cell Line, Tumor; beta Catenin; Feedback; Disease Models, Animal; Quassins
PubMed: 37271476
DOI: 10.1016/j.jare.2023.05.012 -
Natural Product Reports Jun 2020Covering: up to 2020The transcription factor NRF2 is one of the body's major defense mechanisms, driving transcription of >300 antioxidant response element... (Review)
Review
Covering: up to 2020The transcription factor NRF2 is one of the body's major defense mechanisms, driving transcription of >300 antioxidant response element (ARE)-regulated genes that are involved in many critical cellular processes including redox regulation, proteostasis, xenobiotic detoxification, and primary metabolism. The transcription factor NRF2 and natural products have an intimately entwined history, as the discovery of NRF2 and much of its rich biology were revealed using natural products both intentionally and unintentionally. In addition, in the last decade a more sinister aspect of NRF2 biology has been revealed. NRF2 is normally present at very low cellular levels and only activated when needed, however, it has been recently revealed that chronic, high levels of NRF2 can lead to diseases such as diabetes and cancer, and may play a role in other diseases. Again, this "dark side" of NRF2 was revealed and studied largely using a natural product, the quassinoid, brusatol. In the present review, we provide an overview of NRF2 structure and function to orient the general reader, we will discuss the history of NRF2 and NRF2-activating compounds and the biology these have revealed, and we will delve into the dark side of NRF2 and contemporary issues related to the dark side biology and the role of natural products in dissecting this biology.
Topics: Animals; Biological Products; Flavanones; Humans; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Quassins
PubMed: 32400766
DOI: 10.1039/c9np00061e -
Journal of Natural Medicines Oct 2017Human immunodeficiency virus type-1 (HIV-1) is a lentiviral family member that encodes the retroviral Gag, Pol, and Env proteins, along with six additional accessory... (Review)
Review
Human immunodeficiency virus type-1 (HIV-1) is a lentiviral family member that encodes the retroviral Gag, Pol, and Env proteins, along with six additional accessory proteins, Tat, Rev, Vpu, Vif, Nef, and Vpr. The currently approved anti-HIV drugs target the Pol and Env encoded proteins. However, these drugs are only effective in reducing viral replication. Furthermore, the drugs' toxicities and the emergence of drug-resistant strains have become serious worldwide problems. Resistance eventually arises to all of the approved anti-HIV drugs, including the newly approved drugs that target HIV integrase (IN). Drug resistance likely emerges because of spontaneous mutations that occur during viral replication. Therefore, new drugs that effectively block other viral components must be developed to reduce the rate of resistance and suppress viral replication with little or no long-term toxicity. The accessory proteins may expand treatment options. Viral protein R (Vpr) is one of the promising drug targets among the HIV accessory proteins. However, the search for inhibitors continues in anti-HIV drug discovery. In this review, we summarize the naturally occurring compounds discovered from two Myanmar medicinal plants as well as their structure-activity relationships. A total of 49 secondary metabolites were isolated from Kaempferia pulchra rhizomes and Picrasama javanica bark, and the types of compounds were identified as isopimarane diterpenoids and picrasane quassinoids, respectively. Among the isolates, 7 diterpenoids and 15 quassinoids were found to be Vpr inhibitors lacking detectable toxicity, and their potencies varied according to their respective functionalities.
Topics: Anti-HIV Agents; Diterpenes; Gene Products, vpr; HIV-1; Humans; Myanmar; Phytotherapy; Picrasma; Plant Extracts; Plants, Medicinal; Quassins; Structure-Activity Relationship; Virus Replication; Zingiberaceae; vpr Gene Products, Human Immunodeficiency Virus
PubMed: 28681118
DOI: 10.1007/s11418-017-1104-7 -
Virologica Sinica Jun 2023African swine fever (ASF) is an acute, highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry. Unfortunately, there are no...
African swine fever (ASF) is an acute, highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry. Unfortunately, there are no authoritative vaccine and antiviral drug available for ASF control. African swine fever virus (ASFV) is the etiological agent of ASF. Among the ASFV proteins, p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design. Here, we constructed a luciferase reporter system driven by the promoter of p72, which is transcribed by the co-transfected ASFV RNA polymerase complex. Using this system, we screened over 3200 natural product compounds and obtained three potent candidates against ASFV. We further evaluated the anti-ASFV effects and proved that among the three candidates, ailanthone (AIL) inhibits the replication of ASFV at the nanomolar concentration (IC = 15 nmol/L). Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone. Finally, we showed the antiviral activity of AIL on Zika virus and hepatitis B virus (HBV), which supports that AIL is a potential broad-spectrum antiviral agent.
Topics: Transcription, Genetic; Genes, Reporter; Quassins; Antiviral Agents; Capsid Proteins; Animals; Swine; African Swine Fever Virus; African Swine Fever; Luciferases; Drug Evaluation, Preclinical; Biological Products; Promoter Regions, Genetic; Inhibitory Concentration 50; Virus Replication; Humans; HEK293 Cells; Prostaglandin-E Synthases; Zika Virus; Hepatitis B virus
PubMed: 36948461
DOI: 10.1016/j.virs.2023.03.004 -
Journal of the American Chemical Society Jan 2022A synthetic approach to quassinoids is described. The route to the tetracyclic core relies on an efficient and selective annulation between two unsaturated carbonyl...
A synthetic approach to quassinoids is described. The route to the tetracyclic core relies on an efficient and selective annulation between two unsaturated carbonyl components that is initiated by catalytic hydrogen atom transfer from an iron hydride to an alkene. Application of this strategy allows for enantioselective synthesis of quassin, which is prepared in 14 steps from commercially available starting material.
Topics: Quassins; Stereoisomerism
PubMed: 34958202
DOI: 10.1021/jacs.1c12283 -
Molecular Cancer Therapeutics Jan 2020Mutations in genes encoding isocitrate dehydrogenases () 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated exhibit similar...
Mutations in genes encoding isocitrate dehydrogenases () 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against -mutated solid tumor remains unavailable. In this study, we showed that acquisition of mutation results in the disruption of NADP/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in -mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on -mutated cancer and Our findings highlight a possible therapeutic strategy that could be valuable for -mutated cancer treatment.
Topics: Animals; Cell Line, Tumor; Cell Survival; Glioma; Glutathione; Humans; Isocitrate Dehydrogenase; Mice; Mutation; NF-E2-Related Factor 2; Oxidative Stress; Quassins; Reactive Oxygen Species; Xenograft Model Antitumor Assays
PubMed: 31548295
DOI: 10.1158/1535-7163.MCT-19-0103 -
Chemical & Pharmaceutical Bulletin 2019Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and... (Review)
Review
Quassinoids, one kind of triterpenoids with multiple bioactivities such as anti-cancer, anti-malarial, anti-oxidative, anti-microbial, anti-diabetic, anti-viral, and anti-inflammatory effects, have drawn much attention in recent years. Between 2004 and 2018, the structural characteristics and plant sources of 190 quassinoids were reported. Herein, the structure-activity relationships (SARs) of quassinoids along with the anti-cancer mechanisms of four representative quassinoids, eurycomanone, bruceine D, dehydrobruceine B, and brusatol are discussed. This review might be useful for further research and development of quassinoids.
Topics: Antineoplastic Agents, Phytogenic; Antiprotozoal Agents; Antiviral Agents; Cell Survival; Humans; Plants; Plasmodium falciparum; Quassins; Structure-Activity Relationship; Tobacco Mosaic Virus
PubMed: 31257321
DOI: 10.1248/cpb.c18-00958 -
Journal of Experimental & Clinical... Mar 2022Gemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered...
BACKGROUND
Gemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered clinically. Nrf2, an oxidative stress responsive transcription factor, is an important contributor to chemoresistance and poor prognosis of PDAC. Brucein D (BD), a naturally occurring quassinoid, has been reported to exert anti-tumor effect in several cancers including PDAC. In this study, we aimed to investigate the efficacy of BD and the role of Nrf2 axes on the chemosensitivity of GEM and elucidate the underlying molecular mechanisms.
METHODS
Analyses of clinical samples of PDAC and GEPIA database were first conducted to identify the expression of Nrf2 in PDAC. We then established cell lines with stable deletion of Nrf2 through transfecting lentivirus into PDAC cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the expression of Nrf2 in these cell lines. The effects of BD and Nrf2 axes on PDAC cell proliferation, colony-formation, tumor growth and chemosensitivity were determined both in vitro and in vivo. Orthotopic xenograft and genetically engineered KPC mouse models of PDAC were used to evaluate the anti-pancreatic cancer effects of BD and GEM.
RESULTS
Nrf2 was highly expressed in PDAC in the clinical samples and GEPIA analysis. Gain- and lost-function study demonstrated that Nrf2 affected the chemosensitivity of GEM on PDAC cells both in vitro and in vivo. We further found that BD effectively inhibited PDAC cell proliferation and enhanced the chemosensitivity of GEM. Mechanistic studies revealed that BD sensitized GEM in PDAC cells through the ubiquitin-proteasome-dependent degradation of Nrf2, and downregulating the Nrf2 pathway. Silencing of Nrf2 plus BD treatment resulted in more potent inhibitory effects of GEM. In contrast, Nrf2 activation attenuated the chemosensitivity of GEM, indicating that the action of BD was Nrf2 dependent. Finally, the efficacy of BD alone and in combination with GEM on PDAC was validated on both orthotopic xenograft and genetically engineered KPC mouse models.
CONCLUSIONS
BD was able to enhance the chemosensitivity of GEM in PDAC through inhibition of the Nrf2 pathway. Our experimental findings indicate that BD, a potent Nrf2 inhibitor, holds promise for further development into a novel adjuvant therapy for PDAC.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Deoxycytidine; Female; Humans; Mice; Mice, Nude; NF-E2-Related Factor 2; Pancreatic Neoplasms; Quassins; Survival Analysis; Transfection; Gemcitabine
PubMed: 35272669
DOI: 10.1186/s13046-022-02270-z -
Theranostics 2021Aberrant androgen receptor (AR) signaling full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of...
Aberrant androgen receptor (AR) signaling full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.
Topics: Androgen Receptor Antagonists; Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prostatic Neoplasms, Castration-Resistant; Quassins; Receptors, Androgen; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33391515
DOI: 10.7150/thno.51478