ABSTRACT
MAPK pathway regulates the major events including cell division, cell death, migration, invasion, and angiogenesis. Small molecules that modulate the MAPK pathway have been demonstrated to impart cytotoxicity in cancer cells. Herein, the synthesis of a new isoxazolyl-urea derivative (QR-4) has been described and its effect on the growth of pancreatic cancer cells has been investigated. QR-4 reduced the cell viability in a panel of pancreatic cancer cells with minimal effect on normal hepatocytes. QR-4 induced the cleavage of PARP and procaspase-3, reduced the expression of antiapoptotic proteins, increased SubG1 cells, and annexin V/PI-stained cells indicating the induction of apoptosis. QR-4 also triggered paraptosis as witnessed by the reduction of mitochondrial membrane potential, decrease in the expression of Alix, increase in the levels of ATF4 and CHOP, and enhanced ER stress. QR-4 also modulated ferroptosis-related events such as elevation in iron levels, alteration in GSH/GSSG ratio, and increase in the expression of TFRC with a parallel decrease in the expression of GPX4 and SLC7A11. The mechanistic approach revealed that QR-4 increases the phosphorylation of all three forms of MAPKs (JNK, p38, and ERK). Independent application of specific inhibitors of these MAPKs resulted in a partial reversal of QR-4-induced effects. Overall, these reports suggest that a new isoxazolyl-urea imparts cell death via apoptosis, paraptosis, and ferroptosis by regulating the MAPK pathway in pancreatic cancer cells.
ABSTRACT
Deregulated activation of the Wnt/ß-catenin pathway is observed in many types of human malignancies including colon cancer. Abrogation of the Wnt/ß-catenin pathway has been demonstrated as an effective way of inducing cancer cell death. Herein, a new isoxazolyl-urea (QR-5) was synthesized and examined its efficacy on the viability of colon cancer cell lines. QR-5 displayed selective cytotoxicity towards colon cancer cells over normal counterparts. QR-5 induced apoptosis as evidenced by elevation in sub-G1 cells, decrease in Bcl-2, MMP-9, COX-2, VEGF and cleavage of PARP and caspase-3. QR-5 reduced the mitochondrial membrane potential, decreased the expression of Alix and elevated the expression of ATF4 and CHOP indicating the induction of paraptosis. The inhibitor of apoptosis (Z-DEVD-FMK) and paraptosis (CHX) could not restore Alix expression and PARP cleavage in QR-5 treated cells, respectively suggesting the complementation between the two cell death pathways. QR-5 suppressed the expression of Wnt/ß-catenin pathway proteins which was also evidenced by the downregulation of nuclear and cytoplasmic ß-catenin. The dependency of QR-5 on ß-catenin for inducing apoptosis and paraptosis was demonstrated by knockdown experiments using ß-catenin specific siRNA. Overall, QR-5 induces apoptosis as well as paraptosis by mitigating the Wnt/ß-catenin axis in colon cancer cells.
Subject(s)
Apoptosis , Colonic Neoplasms , Urea , Wnt Signaling Pathway , beta Catenin , Humans , Apoptosis/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Colonic Neoplasms/drug therapy , Cell Line, Tumor , beta Catenin/metabolism , Wnt Signaling Pathway/drug effects , Urea/analogs & derivatives , Urea/pharmacology , Membrane Potential, Mitochondrial/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , ParaptosisABSTRACT
INTRODUCTION: Globally, colorectal cancer (CRC) is the third most common type of cancer, and its treatment frequently includes the utilization of drugs based on antibodies and small molecules. The development of CRC has been linked to various signaling pathways, with the Wnt/ß-catenin pathway identified as a key target for intervention. OBJECTIVES: We have explored the impact of imidazopyridine-tethered chalcone-C (CHL-C) in CRC models. METHODS: To determine the influence of CHL-C on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the Wnt/ß-catenin signaling pathway and the anti-cancer effects of CHL-C in vivo were examined in an orthotopic HCT-116 mouse model. RESULTS: We describe the synthesis and biological assessment of the CHL series as inhibitors of the viability of HCT-116, SW480, HT-29, HCT-15, and SNU-C2A CRC cell lines. Further biological evaluations showed that CHL-C induced apoptosis and autophagy in down-regulated ß-catenin, Wnt3a, FZD-1, Axin-1, and p-GSK-3ß (Ser9), and up-regulated p-GSK3ß (Tyr216) and ß-TrCP. In-depth analysis using structure-based bioinformatics showed that CHL-C strongly binds to ß-catenin, with a binding affinity comparable to that of ICG-001, a well-known ß-catenin inhibitor. Additionally, our in vivo research showed that CHL-C markedly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues. CONCLUSION: CHL-C is capable of inducing apoptosis and autophagy by influencing the Wnt/ß-catenin signaling pathway.
ABSTRACT
In wild-type cells, TMEM25 physically associates with EGFR monomer and suppresses the EGFR-mediated STAT3 phosphorylation, which results in the sequestration of unphosphorylated STAT3 in the cytoplasm. In TMEM-/- cells, EGFR monomer phosphorylates STAT3 at the basal level.
ABSTRACT
BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
Subject(s)
Neoplasms , Proto-Oncogene Proteins c-met , Signal Transduction , Humans , Proto-Oncogene Proteins c-met/metabolism , Neoplasms/drug therapy , Signal Transduction/drug effects , Biological Products/pharmacology , Biological Products/therapeutic use , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Bone Neoplasms/metabolismABSTRACT
The discovery of new small molecule-based inhibitors is an attractive field in medicinal chemistry. Structurally diversified heterocyclic derivatives have been investigated to combat multi-drug resistant bacterial infections and they offers several mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming more and more deadly to humans because of its simple method of transmission, quick development of antibiotic resistance, and ability to cause hard-to-treat skin and filmy diseases. The sulfur (SVI) particularly sulfonyl and sulfonamide based heterocyclic moieties, have found to be good anti-MRSA agents. The development of new nontoxic, economical and highly active sulfur (SVI) containing derivatives has become hot research topics in drug discovery research. Presently, more than 150 FDA approved Sulfur (SVI)-based drugs are available in the market, and they are widely used to treat various types of diseases with different therapeutic potential. The present collective data provides the latest advancements in Sulfur (SVI)-hybrid compounds as antibacterial agents against MRSA. It also examines the outcomes of in-vitro and in-vivo investigations, exploring potential mechanisms of action and offering alternative perspectives on the structure-activity relationship (SAR). Sulfur (SVI)-hybrids exhibits synergistic effects with existing drugs to provide antibacterial action against MRSA.
Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Structure-Activity Relationship , Sulfur/pharmacologyABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directs the transcription of genes involved in the promotion of cell survival and proliferation, inflammation, angiogenesis, invasion, and migration. Overactivation of STAT3 is often witnessed in human cancers, thereby making it a good target in oncology. Herein the efficacy of Leonurine (Leo), a bioactive alkaloid present in Herba leonuri, was investigated for its STAT3-inhibitory potential in hepatocellular carcinoma (HCC) cells. Leo downregulated the persistent as well as IL-6-driven activation of STAT3. Leo abrogated the nuclear localization and DNA interacting ability of STAT3. Leo was also found to impart STAT3 inhibition by mitigating the activation of upstream kinases such as JAK1, JAK2, and Src both in constitutive and IL-6 inducible systems. Leo curbed the STAT3-driven luciferase gene expression and the depletion of STAT3 resulted in the reduced responsiveness of HCC cells to Leo. Pervanadate exposure counteracted Leo-induced STAT3 inhibition suggesting the involvement of a protein tyrosine phosphatase. SHP-1 was significantly elevated upon Leo exposure whereas the depletion of SHP-1 was found to revert the effect of Leo on STAT3. Leo induced apoptosis and also significantly potentiated the cytotoxic effect of paclitaxel, doxorubicin, and sorafenib. Leo was found to be non-toxic up to the dose of 10 mg/kg in NCr nude mice. In conclusion, Leo was demonstrated to induce cytotoxicity in HCC cells by mitigating the persistent of activation of STAT3 pathway.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Mice , Humans , Carcinoma, Hepatocellular/pathology , STAT3 Transcription Factor/metabolism , Liver Neoplasms/pathology , Signal Transduction , Up-Regulation , Mice, Nude , Interleukin-6/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , ApoptosisABSTRACT
The hypoxic environment is prominently witnessed in most solid tumors and is associated with the promotion of cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, metabolic reprogramming, therapeutic resistance, and metastasis of tumor cells. All the effects are mediated by the expression of a transcription factor hypoxia-inducible factor-1α (HIF-1α). HIF-1α transcriptionally modulates the expression of genes responsible for all the aforementioned functions. The stability of HIF-1α is regulated by many proteins and non-coding RNAs (ncRNAs). In this article, we have critically discussed the crucial role of ncRNAs [such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), Piwi-interacting RNAs (piRNAs), and transfer RNA (tRNA)-derived small RNAs (tsRNAs)] in the regulation of stability and expression of HIF-1α. We have comprehensively discussed the molecular mechanisms and relationship of HIF-1α with each type of ncRNA in either promotion or repression of human cancers and therapeutic resistance. We have also elaborated on ncRNAs that are in clinical examination for the treatment of cancers. Overall, the majority of aspects concerning the relationship between HIF-1α and ncRNAs have been discussed in this article.
Subject(s)
MicroRNAs , Neoplasms , Humans , Cell Proliferation/genetics , Drug Resistance, Neoplasm/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , RNA, Untranslated/geneticsABSTRACT
The use of photocatalysts without noble metals is of great interest in the industrial field for the degradation of organic pollutants. In this study, a CuO/ZnO heterostructure was synthesized using the microwave hydrothermal method and characterized using various analytical techniques. The synthesized CuO/ZnO photocatalyst exhibited a low bandgap energy of 2.4 eV, enabling efficient visible light absorption. The photocatalytic activity of the CuO/ZnO heterostructure was evaluated for the degradation of Methyl Orange (MO) dye and showed a high degradation efficiency of 99 % due to its excellent electron-hole charge separation. The biological activity of the synthesized CuO/ZnO catalyst was further investigated through protein docking studies, which showed promising results. The CuO/ZnO was also evaluated for its anticancer and antibacterial properties. It exhibited effective anticancer activity against prostate cancer cells (PC-3) in a dose-dependent manner, with an IC50 value of 6.87 ± 8. In addition, it demonstrated potent antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus cereous and Pseudomonas aeruginola. The results of this study demonstrate the potential of CuO/ZnO heterostructures as promising materials for various applications in the fields of photocatalysis, biomedicine and antimicrobial materials. Future research in this area will focus on further optimizing the properties of the CuO/ZnO heterostructure to enhance its performance in these applications.
ABSTRACT
An easily adaptable protocol for the preparation of 5-hydroxy-1H-pyrrol-2(5H)-ones from readily available starting materials has been reported. The reaction of sulfur ylides with carbonyl compounds is a common approach to synthesizing epoxides. Alternatively, we have developed a method with mild reaction conditions wherein sulfur ylide underwent an intramolecular cyclization with a ketonic carbonyl group in a highly efficient way and was followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in excellent yields. The present method offers a straightforward approach to synthesize 5-hydroxy-1H-pyrrol-2(5H)-ones from sulfur ylides without the aid of transition metal in one-pot operation, which involves sequential cyclization and rearrangement reaction. The formation of 5-hydroxy-1H-pyrrol-2(5H)-ones is supported by different spectroscopic techniques, including X-ray crystallographic data and 2D NMR studies (COSY, HSQC, HMBC, and DEPT).
ABSTRACT
A new approach for the synthesis of two important annulated pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives from multicomponent reactions was achieved by using T3P®-DMSO-catalysed reactions of stable alcohols, cyclic 1,3-dicarbonyl compounds and amino derivatives of phenyl pyrazoles and isoxazole and has been reported for the first time. This reaction occurred via a tandem oxidative-condensation reaction under microwave irradiation and notable characteristics of this protocol are MCR reactions, shorter reaction time, less waste creation, ease of workup, stable precursors, broad substrate scope and functional group tolerance.
ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5-mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl-indolo-quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3-difluoro-6-((1-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)methyl)-6H-indolo[2,3-b]quinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin-V-fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699 . DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI-driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK-STAT pathway. Knockdown of PTPεC suppressed the DTI-induced STATs inhibition in GC cells. Taken together, triazolyl-indolo-quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells.
Subject(s)
Signal Transduction , Stomach Neoplasms , Humans , STAT5 Transcription Factor/metabolism , STAT5 Transcription Factor/pharmacology , STAT3 Transcription Factor/metabolism , DNA-Binding Proteins/metabolism , Trans-Activators , Up-Regulation , Quinoxalines/pharmacology , Janus Kinases/metabolism , Janus Kinases/pharmacology , STAT Transcription Factors/metabolism , STAT Transcription Factors/pharmacology , Phosphorylation , ApoptosisABSTRACT
BACKGROUND: Indazoles are known for their anti-cancer properties. OBJECTIVE: The current investigation was on the synthesis and evaluation of novel indazole derivatives for their anticancer properties. METHODS: A series of novel indazoles were synthesized and characterized by IR, NMR and LCMS. We performed cytotoxic studies for all synthesized compounds on different cell lines such as HeLa, MCF-7 and EAC using MTT assay. The lead compound was tested further for its anti-tumor and anti-angiogenic effect on EAT tumor model. RESULTS: Amongst the series of compounds synthesized, compound KA8 showed potent antiproliferative effect against Hela, MCF-7 and EAC cell lines with IC50 values 10.4 to 11.5 and 13.5 µM respectively. In addition, our compound KA8 significantly decreased the cell viability, body weight, ascites volume and it also showed superior survival ability of mice compared to control groups. Furthermore, it suppressed the formation of neovasculature in the peritoneum of EAT-bearing mice. CONCLUSION: The findings reveal that the lead compound KA8 possesses potent anti-tumor and anti-angiogenic properties thereby promising it to be developed as a novel anticancer agent with further mechanistic studies.
Subject(s)
Antineoplastic Agents , Carcinoma, Ehrlich Tumor , Animals , Mice , Cell Line, Tumor , Indazoles/chemistry , Ascites/drug therapy , Cell Proliferation , Antineoplastic Agents/chemistry , Carcinoma, Ehrlich Tumor/drug therapy , Drug Screening Assays, Antitumor , Molecular Structure , Structure-Activity RelationshipABSTRACT
Environmental factors such as exposure to ionizing radiations, certain environmental pollutants, and toxic chemicals are considered as risk factors in the development of breast cancer. Triple-negative breast cancer (TNBC) is a molecular variant of breast cancer that lacks therapeutic targets such as progesterone receptor, estrogen receptor, and human epidermal growth factor receptor-2 which makes the targeted therapy ineffective in TNBC patients. Therefore, identification of new therapeutic targets for the treatment of TNBC and the discovery of new therapeutic agents is the need of the hour. In this study, CXCR4 was found to be highly expressed in majority of breast cancer tissues and metastatic lymph nodes derived from TNBC patients. CXCR4 expression is positively correlated with breast cancer metastasis and poor prognosis of TNBC patients suggesting that suppression of CXCR4 expression could be a good strategy in the treatment of TNBC patients. Therefore, the effect of Z-guggulsterone (ZGA) on the expression of CXCR4 in TNBC cells was examined. ZGA downregulated protein and mRNA expression of CXCR4 in TNBC cells and proteasome inhibition or lysosomal stabilization had no effect on the ZGA-induced CXCR4 reduction. CXCR4 is under the transcriptional control of NF-κB, whereas ZGA was found to downregulate transcriptional activity of NF-κB. Functionally, ZGA downmodulated the CXCL12-driven migration/invasion in TNBC cells. Additionally, the effect of ZGA on growth of tumor was investigated in the orthotopic TNBC mice model. ZGA presented good inhibition of tumor growth and liver/lung metastasis in this model. Western blotting and immunohistochemical analysis indicated a reduction of CXCR4, NF-κB, and Ki67 in tumor tissues. Computational analysis suggested PXR agonism and FXR antagonism as targets of ZGA. In conclusion, CXCR4 was found to be overexpressed in majority of patient-derived TNBC tissues and ZGA abrogated the growth of TNBC tumors by partly targeting the CXCL12/CXCR4 signaling axis.
Subject(s)
Liver Neoplasms , Pregnenediones , Triple Negative Breast Neoplasms , Mice , Animals , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Signal Transduction , Cell Line, Tumor , Chemokine CXCL12/genetics , Receptors, CXCR4/geneticsABSTRACT
Plants have been used for therapeutic purposes against various human ailments for several centuries. Plant-derived natural compounds have been implemented in clinics against microbial diseases. Unfortunately, the emergence of antimicrobial resistance has significantly reduced the efficacy of existing standard antimicrobials. The World Health Organization (WHO) has declared antimicrobial resistance as one of the top 10 global public health threats facing humanity. Therefore, it is the need of the hour to discover new antimicrobial agents against drug-resistant pathogens. In the present article, we have discussed the importance of plant metabolites in the context of their medicinal applications and elaborated on their mechanism of antimicrobial action against human pathogens. The WHO has categorized some drug-resistant bacteria and fungi as critical and high priority based on the need to develope new drugs, and we have considered the plant metabolites that target these bacteria and fungi. We have also emphasized the role of phytochemicals that target deadly viruses such as COVID-19, Ebola, and dengue. Additionally, we have also elaborated on the synergetic effect of plant-derived compounds with standard antimicrobials against clinically important microbes. Overall, this article provides an overview of the importance of considering phytogenous compounds in the development of antimicrobial compounds as therapeutic agents against drug-resistant microbes.
ABSTRACT
Epithelial-mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self-renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss-of-epithelial cell polarity, cell-cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gain-of-expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/ß-catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor-ß pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor-derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor-derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant-derived natural products, their semi-synthetic derivatives, and nano-formulations that are described as promising EMT blockers.
Subject(s)
Epithelial-Mesenchymal Transition , Neoplasms , Humans , Epithelial-Mesenchymal Transition/genetics , Phosphatidylinositol 3-Kinases/metabolism , Hedgehog Proteins/metabolism , Neoplasms/metabolism , Transcription Factors , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Tumor MicroenvironmentABSTRACT
Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.
Subject(s)
Gastrointestinal Neoplasms , MicroRNAs , RNA, Long Noncoding , Humans , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Gastrointestinal Neoplasms/genetics , Signal Transduction , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolismABSTRACT
Highly regioselective synthesis of 2-acyl-4-(het)arylthiazoles and thioethers by the reaction between α-oxothioamides and α-bromoketones in the absence of base in DMF and in the presence of triethylamine in acetonitrile, respectively, has been reported. This thiazole synthesis is an important extended work of the Hantzsch thiazole synthesis, which overcomes the drawbacks of earlier reported methods. The probable mechanisms for the formation of thiazoles and thioethers are also presented.
ABSTRACT
Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly-derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.
Subject(s)
Neoplasms , Receptors, Cytoplasmic and Nuclear , Humans , Transcription Factors , Neoplasms/drug therapy , Signal TransductionABSTRACT
Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6-diamino-2-mercaptopyrimidin-4-ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27-fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV-dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double-strand breaks inside cells, and improved anti-cancer potential when combined with γ-radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics.