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AIM: To summarise a detailed up-to-date review of the traditional uses, phytoconstituents, and pharmacological activities of various parts of Kigelia africana. MATERIALS AND METHODS: Google Scholar, PubMed, PubChem, Elsevier, King Draw, indianbiodiversity.org. RESULT: The phytochemical analysis of Kigelia africana subsp. africana has revealed the presence of approximately 145 compounds extracted from different parts of the plant. These bioactive extracts of the plant possess anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antineoplastic, and anti-urolithic activities. Due to its anti-inflammatory, antioxidant, and immune-booster properties, Kigelia can prove to be an essential source of drugs for treating various disorders. CONCLUSION: Knowledge of the phytoconstituents, non-medicinal and medicinal traditional uses, pharmacological activities, and products obtained from Kigelia is described in this review with the hope that the updated findings will promote research on its biological pathways.
Traditional medicinal importance of Kigelia africana subsp. africanaPhytoconstituents present in extracts from different parts of the plantPharmacological activities of phytochemicals extracted from KigeliaAnti-inflammatory and antioxidant role in preventing oxidative stressPotential as ethnopharmacological therapeutic in treating respiratory ailmentsToxicity evaluation of Kigelia africana subsp. africana.
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BACKGROUND: Breast cancer is a multifactorial disease which involves number of molecular factors that are critically involved in proliferation of breast cancer cells. MEN1 gene that is traditionally known for its germline mutations in neuroendocrine tumors is associated with high risk of developing breast cancer in females with MEN1 syndrome. However, the paradoxical role of MEN1 is reported in sporadic breast cancer cases. The previous studies indicate the functional significance of MEN1 in regulating breast cells proliferation but its relevance in development and progression of breast cancer is still not known. Our study targets to find the role of MEN1 gene aberration and its clinical significance in breast cancer. METHODS: Breast tumor and adjacent normal tissue of 142 sporadic breast cancer patients were collected at the time of surgery. The expression analysis of MEN1 mRNA and protein was done through RT-PCR, immunohistochemistry and western blotting. Further to find the genetic and epigenetic alterations, automated sequencing and MS-PCR was performed respectively. Correlation between our findings and clinical parameters was determined using appropriate statistical tests. RESULTS: MEN1 expression was found to be significantly increased in the breast tumor tissue with its predominant nuclear localization. The elevated expression of MEN1 mRNA (63.38% cases) and protein (60.56% cases) exhibited a significant association with ER status of the patients. Most of the cases had unmethylated (53.52%) MEN1 promoter region, which can be a key factor responsible for dysregulated expression of MEN1 in breast cancer cases. Our findings also revealed the significant association of MEN1 mRNA overexpression with Age and lymph node status of the patients. CONCLUSION: Our results indicate upregulated expression of MEN1 in sporadic breast cancer patients and it could be critically associated with development and advancement of the disease.
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Neoplasias da Mama , Proteínas Proto-Oncogênicas , Feminino , Humanos , Neoplasias da Mama/genética , Relevância Clínica , Expressão Gênica , RNA Mensageiro/genética , Proteínas Proto-Oncogênicas/genéticaRESUMO
For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.
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Cancer cells ferment glucose, even under aerobic conditions, following a phenomenon known as the 'Warburg effect.' Hexokinase 2 (HK2) catalyzes the crucial step of phosphorylation of glucose for subsequent utilization in glycolysis and other pathways. HK2 has been proposed as a potential therapeutic target for anti-cancer therapy because of its enhanced expression in glucose-dependent tumors. Here, we have employed structure-based virtual screening using in-house library to identify potential phytoconstituents which could inhibit the HK2 activity. The initial hits were selected based on their binding affinity towards HK2 using the molecular docking approach. Subsequently, the filters for physicochemical properties, PAINS patterns and PASS evaluation were applied to find potential hits against HK2. Finally, we have identified epigallocatechin gallate (EGCG) and quercitrin, two natural compounds with appreciable binding affinity, efficiency and specificity towards the HK2 binding pocket. Both compounds were found to be binding preferentially to the HK2 active site and showed a decent set of drug-like properties. All-atom molecular dynamics (MD) simulations for 100 ns were carried out to see the conformational dynamics, complexes stability and interaction mechanism of HK2 with EGCG and quercitrin. MD simulation results showed that HK2 forms stable protein-ligand complexes with EGCG and quercitrin with consistency throughout the trajectory. Overall, these findings suggest that EGCG and quercitrin might be further exploited as promising scaffolds in the drug development process against HK2..Communicated by Ramaswamy H. Sarma.
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Hexoquinase , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Ligantes , GlucoseRESUMO
The metabolism of cancer is remarkably different from that of normal cells and confers a variety of benefits, including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefits. In the continued search for safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and attempt to make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the pharmacological interactions of phytocompounds with major metabolic pathways and evaluate the role of phytocompounds in the regulation of growth signaling and transcriptional programs involved in the metabolic transformation of cancer. Lastly, we examine the potential of these compounds in the clinical management of cancer along with limitations and challenges.
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ETHNOPHARMACOLOGICAL RELEVANCE: Synthetic drugs used for cancer treatment have side effects that may be immunosupressive, can cause liver, kidney and cardiac toxicity, and infertility and ovarian failure, among others. Thus, herbal drugs could be used in the cancer treatment as an adjuvant therapy. Andrographis paniculata (Burm.f.) Nees (AP) is one of the traditional herbs used in different alternative medicinal systems such as Ayurveda, Unani, Chinese, Malayi, Siddha, etc. for the treatment of various disorders and diseases including cancer. AIM OF THE STUDY: The aim of writing this review is to highlight the medicinal importance of AP and its main phytoconstituent andrographolide (AG). The main emphasis was given on the anticancer activity of AG, its proposed mechanisms of action, novel approaches used to improve its biopharmaceutical properties with the perspective of evidence-based research, and its development as an adjuvant therapy for cancer treatment in future. MATERIALS AND METHODS: Literature survey was conducted and research papers were retrieved from different databases such as Pubmed, Google Scholar, ACS, Wiley online library, ScienceDirect, Springer, and Scopus during 1970-2020. Research articles, review articles, and short communications, etc. were used for this purpose. The papers were selected on the basis of exclusion and inclusion criteria. RESULTS: Different anticancer mechanisms of AG have been reportedly proven such as cell cycle arrest, apoptosis, NF-κß inhibition, antiangiogenesis, cytokine inhibition, etc. whereas its pharmacokinetic properties showed its highly protein bound nature, Cyt P400 (CYP) inhibition, low aqueous solubility, poor oral bioavailability, etc. Different novel formulations of AG have been investigated to increase its bioavailability for better efficacy. CONCLUSION: This review can provide knowledge about the potential applicability of AP or AG as an adjuvant therapy in cancer treatment. Further research is needed before making any conclusion about the efficacy in humans as an adjuvant therapy in cancer.
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Andrographis/química , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Composição de Medicamentos , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment modalities and poor prognosis. Metabolic reprogramming in cancer is considered a hallmark of therapeutic relevance. Here, we report disruption of metabolic reprogramming in TNBC cells by silibinin via modulation of EGFR-MYC-TXNIP signaling. Metabolic assays combined with LC-MS-based metabolomics revealed inhibition of glycolysis and other key biosynthetic pathways by silibinin, to induce metabolic catastrophe in TNBC cells. Silibinin-induced metabolic suppression resulted in decreased cell biomass, proliferation, and stem cell properties. Mechanistically, we identify EGFR-MYC-TXNIP as an important regulator of TNBC metabolism and mediator of inhibitory effects of silibinin. Highlighting the clinical relevance of our observations, the analysis of METABRIC dataset revealed deregulation of EGFR-MYC-TXNIP axis in TNBC and association of EGFRhigh -MYChigh -TXNIPlow signature with aggressive glycolytic metabolism and poor disease-specific and metastasis-free survival. Importantly, combination treatment of silibinin or 2-deoxyglucose (glycolysis inhibitor) with paclitaxel synergistically inhibited proliferation of TNBC cells. Together, our results highlight the importance of EGFR-MYC-TXNIP axis in regulating TNBC metabolism, demonstrate the anti-TNBC activity of silibinin, and argue in favor of targeting metabolic vulnerabilities of TNBC, at least in combination with mainstay chemotherapeutic drugs, to effectively treat TNBC patients.
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Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/genética , Proteínas Proto-Oncogênicas c-myc/genética , Silibina/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Desoxiglucose/farmacologia , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glicólise/efeitos dos fármacos , Glicólise/genética , Humanos , Metaboloma/efeitos dos fármacos , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Andrographolide and neoandrographolide are major bioactive molecules of Andrographis paniculata, a well-known medicinal plant. These molecules exhibited varying degrees of anti-inflammatory and anticancer activities in-vitro and in-vivo. Role of begomovirus protein C2/TrAP in biosynthesis of andrographolide was identified through molecular modeling, docking and predicted results were substantiated by in vitro studies. Homology molecular modeling and molecular docking were performed to study the binding conformations and different bonding behaviors, in order to reveal the possible mechanism of action behind higher accumulation of andrographolide. It was concluded that C2/TrAP inhibit the activation of SNF1-Related Protein Kinase-1 (SnRK1) in terpenoid pathway and removes the negative regulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) by SnRK1, leading to higher accumulation of andrographolide and neoandrographolide in begomovirus infected plants. The binding site residues of SnRK1 docked with C2/TrAP were found to be associated with ATP binding site, substrate binding site and activation loop. Predicted results were also validated by HPTLC. This study provides important insights into understanding the role of viral protein in altering the regulation of biosynthesis of andrographolide and could be used in future research to develop biomimetic methods for increasing the production of such phytometabolites having anti-cancerous and anti-inflammatory properties.