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Chemotherapy with doxorubicin (Dox) can lead to cardiotoxic effects, presenting a major complication in cancer therapy. Diindolylmethane (DIM), derived from cruciferous vegetables like cabbage, exhibits numerous health benefits. However, its clinical application is limited because of low bioavailability and suboptimal natural concentrations in dietary sources. To address this limitation, we developed a processing methodology, specifically fermentation and boiling, to enhance DIM levels in cabbage. High-performance liquid chromatography (HPLC) analysis revealed a threefold DIM increase in fermented cabbage and a substantial ninefold increase in fermented-boiled cabbage compared to raw cabbage. To evaluate the clinical implications, we formulated a DIM-enriched diet and administered it to mice undergoing Dox treatment. Our in vivo results revealed that Dox treatment led to cardiotoxicity, manifested by changes in body and heart weight, increased mortality, and severe myocardial tissue degeneration. Dietary administration of the DIM-enriched diet enhanced antioxidant defenses and inhibited apoptosis in the cardiac tissue by interfering with mitoptosis and increasing antioxidant enzyme expression. Interestingly, we found that the DIM-enriched diet inhibited the nuclear translocation of NF-kB in cardiac tissue, thereby downregulating the expression of inflammatory mediators such as TNF-α and IL-6. Further, the DIM-enriched diet significantly reduced serum cardiac injury markers elevated by Dox treatment. These results suggest that the DIM-enriched cabbage diet can serve as a complementary dietary intervention for cancer patients undergoing chemotherapy. Further, our research highlights the role of plant-based diets in reducing treatment side effects and improving the quality of life for cancer patients.
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Brassica , Cardiotoxicidad , Doxorrubicina , Indoles , Animales , Doxorrubicina/toxicidad , Brassica/química , Ratones , Masculino , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Antibióticos Antineoplásicos/toxicidadRESUMEN
Tumor angiogenesis is primarily regulated by vascular endothelial growth factor and its receptor (VEGF-VEGFR) communication, which is involved in cancer cell growth, progression, and metastasis. Diindolylmethane (DIM), a dietary bioactive from cruciferous vegetables, has been extensively studied in preclinical models for breast cancer prevention and treatment. Nevertheless, the possible role of DIM in the angiogenesis and metastasis regulations in triple-negative breast cancer (TNBC) remains elusive. Here, we investigated the potential anti-angiogenic and anti-metastatic role of DIM in combination with centchroman (CC). We observed that the oral administration of the DIM and CC combination suppressed primary tumor growth and tumor-associated vascularization in 4T1 tumors. Further, the DIM and CC combination exhibited a strong inhibitory effect on VEGF-induced angiogenesis in matrigel plugs. The mechanistic study demonstrated that DIM and CC could effectively downregulate VEGFA expression in tumor tissue and strongly interact with VEGFR2 to block its kinase activity. Interestingly, the DIM and CC combination also suppressed the lung metastasis of the highly metastatic 4T1 tumors through the downregulation of FAK/MMP9/2 signaling and reversal of epithelial-to-mesenchymal transition (EMT). Overall, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating TNBC.
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Centcromano , Neoplasias de la Mama Triple Negativas , Humanos , Centcromano/farmacología , Centcromano/uso terapéutico , Línea Celular Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Proliferación CelularRESUMEN
Diindolylmethane (DIM) is a key metabolite of indole-3-carbinol found in cruciferous vegetables such as broccoli, cauliflower, and cabbage. DIM has been known for its anti-cancerous activity through various mechanisms. Most cancer cells, including triple-negative breast cancer (TNBC), adapt distinct metabolic reprogramming for rapid growth and proliferation. Hence, targeting metabolic dysregulation may provide a favorable therapeutic condition for the treatment of TNBC. Earlier, we found that DIM increases the intracellular accumulation of Centchroman (CC), a potential anticancer agent, thereby enhancing the therapeutic potential of CC against breast cancer. However, the role of DIM in regulating TNBC cellular metabolism remains unknown. In the current study, we investigated the potential therapeutic interventions of DIM in TNBC and its metabolic reprogramming in enhancing the efficacy of CC. We found that DIM induced metabolic catastrophe in TNBC cells by regulating aerobic glycolysis and intermediate metabolism. Further, the DIM and CC combination significantly inhibited the TNBC tumor growth in the 4T1-syngeneic model. The inhibition of tumor growth was associated with the downregulation of key aerobic glycolysis mediators such as PKM2, GLUT1, and hypoxia-inducible factor 1α (HIF-1α). This is a first-of-a-kind investigation linking DIM with aerobic glycolysis regulation and enhancing the treatment efficacy of CC against TNBC. Therefore, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating metabolically dysregulated TNBC.
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P-glycoprotein (P-gp), a transmembrane glycoprotein, is mainly involved in lung cancer multidrug resistance. Several P-gp inhibitors have been developed to enhance the efficacy of chemotherapeutics and overcome drug resistance. However, most of them failed in the clinical stages due to undesirable side effects. Therefore, there is a requirement to develop P-gp inhibitors from natural sources. Dietary spice bioactives have been well-known for their anticancer activities. However, their role in modulating the P-gp activity has not been well investigated. Therefore, we have screened for the potential bioactives from various spice plants with P-gp modulatory activity using computational molecular docking analysis. The computational analysis revealed several key bioactives from curry leaves, specifically mahanimbine, exhibited a strong binding affinity with P-gp. Unfortunately, mahanimbine is available with few commercial sources at very high prices. Therefore, we prepared a curry leaves extract and isolated mahanimbine by a novel, yet simple, extraction method that requires less time and causes minimum environmental hazards. After purification, structure, and mass were confirmed for the isolated compound by IR spectrum and LC-MS/MS analysis, respectively. In the mechanistic study, hydrolysis of ATP and substrate efflux by P-gp are coupled. Hence, ATP binding at the ATPase-binding site is one of the fundamental steps for the P-gp efflux cycle. We found that mahanimbine demonstrated to stimulate P-gp ATPase activity. Concurrently, it enhanced the intracellular accumulation of P-gp substrates Rhodamine 123 and Hoechst stain, which indicates that mahanimbine modulates the function of P-gp. In addition, we have analyzed the complementary effect of mahanimbine with the chemotherapeutic drug gefitinib. We found that mahanimbine synergistically enhanced gefitinib efficiency by increasing its intracellular accumulation in lung cancer cells. Overall, mahanimbine has been shown to be a potent P-gp modulator. Therefore, mahanimbine can be further developed as a potential candidate to overcome chemoresistance in lung cancer.
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Neoplasias Pulmonares , Murraya , Humanos , Murraya/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Resistencia a Antineoplásicos , Simulación del Acoplamiento Molecular , Gefitinib/farmacología , Cromatografía Liquida , Espectrometría de Masas en Tándem , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Adenosina Trifosfato , Adenosina Trifosfatasas/metabolismo , Línea Celular TumoralRESUMEN
BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Dietary bioactives have been used as alternative therapeutics to overcome various adverse effects caused by chemotherapeutics. Curry leaves are a widely used culinary spice and different parts of this plant have been used in traditional medicines. Curry leaves are a rich source of multiple bioactives, especially polyphenols and alkaloids. Therefore, extraction processes play a key role in obtaining the optimum yield of bioactives and their efficacy. PURPOSE: We aim to select an extraction process that achieves the optimum yield of bioactives in curry leaves crude extract (CLCE) with minimum solvent usage and in a shorter time. Further, to investigate the anticancer properties of CLCE and its mechanism against lung cancer. METHODS: Different extraction processes were performed and analyzed polyphenol content. The bioactives and essential oils present in curry leaves were identified through LC-MS/MS and GC-MS analysis. The cytotoxicity of microwave-assisted CLCE (MA-CLCE) was investigated through MTT and colony-forming assays. The DNA damage was observed by comet assay. The apoptotic mechanisms of MA-CLCE were investigated by estimating ROS production, depolarization of mitochondrial membrane potential (MMP), and apoptotic proteins. The glutathione assay estimated the antioxidant potential of MA-CLCE in normal cells. RESULTS: Generally, conventional extraction methods require high temperatures, extra energy input, and time. Recently, green extraction processes are getting wider attention as alternative extraction methods. This study compared different extraction processes and found that the microwave-assisted extraction (MAE) method yields the highest polyphenols from curry leaves among other extraction processes with minimum processing. The MA-CLCE functions as an antioxidant under normal physiological conditions but pro-oxidant to cancer cells. MA-CLCE scavenges free radicals and enhances the intracellular GSH level in alveolar macrophages in situ. We found that MA-CLCE selectively inhibits cell proliferation and induces apoptosis in cancer cells by altering cellular redox status. MA-CLCE induces chromatin condensation and genotoxicity through ROS-induced depolarization of MMP. The depolarization of MMP causes the release of cytochrome c into the cytosol and activates the apoptotic pathway in lung cancer cells. However, pretreatment with ascorbic acid, an antioxidant, inhibits the MA-CLCE-induced apoptosis by reducing ROS production, which impedes mitochondrial membrane disruption, preventing BAX/BCL-2 expression alteration. Simultaneously, MA-CLCE downregulates the expression of survival signaling regulator PI3K/AKT, which modulates Nrf-2. MA-CLCE also diminishes intracellular antioxidant proficiency by suppressing Nrf-2 expression, followed by HO-1 expressions. CONCLUSION: Among several extraction methods, MA-CLCE is rich in several bioactives, especially polyphenols, alkaloids, and essential oils. Here, we reported for the first time that MA-CLCE functions as a pro-oxidant to lung cancer cells and acts as an antioxidant to normal cells by regulating different cellular programs and signaling pathways. Therefore, it can be further developed as a promising phytomedicine against lung cancer.
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Alcaloides , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Murraya , Aceites Volátiles , Alcaloides/farmacología , Antioxidantes/metabolismo , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Caspasa 3/metabolismo , Cromatografía Liquida , Inestabilidad Genómica , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Murraya/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Aceites Volátiles/farmacología , Oxidación-Reducción , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Polifenoles/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Espectrometría de Masas en TándemRESUMEN
Chemoresistance is one of the major challenges in the treatment of breast cancer. Recent evidence suggests that epithelial-to-mesenchymal transition (EMT) plays a critical role in not only metastasis but also in chemoresistance, hence causing tumor relapse. This study aimed to identify the hub genes associated with EMT and chemoresistance in breast cancer affecting patient/clinical survival. Commonly differentially expressed genes (DEGs) during EMT and chemoresistance in breast cancer cells were identified using publicly available datasets, GSE23655, GSE39359, GSE33146 and GSE76540. Hierarchical clustering analysis was utilized to determine the commonly DEGs expression pattern in chemoresistant (CR) breast cancer cells. GSEA revealed that EMT-related genes sets were enriched in the CR samples. Further, we found that EMT-induced breast cancer cells showed overexpression of drug efflux transporters along with resistance to chemotherapeutic drug. Pathway enrichment analysis revealed that the commonly DEGs were enriched in immunological pathways, early endosome, protein dimerization, and proteoglycans in cancer. Further, we identified eight hub genes from the protein-protein interaction (PPI) network. We validated the gene expression levels of the hub genes among TCGA breast cancer samples using UALCAN. Survival analysis for the hub genes was performed using KM plotter, which showed a worse relapse-free survival (RFS) of the hub genes among breast cancer patients. In conclusion, this study identified eight hub genes that play an important role in the pathways underlying EMT-induced chemoresistance in breast cancer and can be used as therapeutic targets after clinical validation.
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Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Análisis por Conglomerados , Biología Computacional/métodos , Bases de Datos Genéticas , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Mapas de Interacción de Proteínas/genética , Análisis de SupervivenciaRESUMEN
Chemoresistance is a major hindrance in cancer chemotherapies, a leading cause of tumor recurrence and cancer-related deaths. Cancer cells develop numerous strategies to elude immune attacks and are regulated by immunological factors. Cancer cells can alter the expression of several immune modulators to upregulate the activities of immune checkpoint pathways. Targeting the immune checkpoint inhibitors is a part of the cancer immunotherapy altered during carcinogenesis. These immune modulators have the capability to reprogram the tumor microenvironment, thereby change the efficacy of chemotherapeutics. In general, the sensitivity of drugs is reduced in the immunosuppressive tumor microenvironment, resulting in chemoresistance and tumor relapse. The regulation of microRNAs (miRNAs) is well established in cancer initiation, progression, and therapy. Intriguingly, miRNA affects cancer immune surveillance and immune response by targeting immune checkpoint inhibitors in the tumor microenvironment. miRNAs alter the gene expression at the post-transcriptional level, which modulates both innate and adaptive immune systems. Alteration of tumor immune microenvironment influences drug sensitivity towards cancer cells. Besides, the expression profile of immune-modulatory miRNAs can be used as a potential biomarker to predict the response and clinical outcomes in cancer immunotherapy and chemotherapy. Recent evidences have revealed that cancer-derived immune-modulatory miRNAs might be promising targets to counteract cancer immune escape, thereby increasing drug efficacy. In this review, we have compiled the role of miRNAs in overcoming the chemoresistance by modulating tumor microenvironment and discussed their preclinical and clinical implications.
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MicroARNs , Neoplasias , Resistencia a Antineoplásicos/genética , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , MicroARNs/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Epigenetic modifications are heritable yet reversible, essential for normal physiological functions and biological development. Aberrant epigenetic modifications, including DNA methylation, histone modification, and non-coding RNA (ncRNA)-mediated gene regulation play a crucial role in cancer progression. In cellular reprogramming, irregular epigenomic modulations alter cell signaling pathways and the expression of tumor suppressor genes and oncogenes, resulting in cancer growth and metastasis. Therefore, alteration of epigenetic-status in cancer cells can be used as a potential target for cancer therapy. Several synthetic epigenetic inhibitors (epi-drugs) and natural epigenetic modulatory bioactives (epi-diets) have been shown to have the potential to alter the aberrant epigenetic status and inhibit cancer progression. Further, the use of combinatorial approaches with epigenetic drugs and diets has brought promising outcomes in cancer prevention and therapy. In this article, we have summarized the epigenetic modulatory activities of epi-drugs, epi-diets, and their combination against various cancers. We have also compiled the preclinical and clinical status of these epigenetic modulators in different cancers.
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Epigenómica , Neoplasias , Metilación de ADN , Dieta , Epigénesis Genética , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/prevención & controlRESUMEN
COVID-19 is an infectious pandemic caused by the SARS-CoV-2 virus. The critical components of SARS-CoV-2 are the spike protein (S-protein) and the main protease (Mpro). Mpro is required for the maturation of the various polyproteins involved in replication and transcription. S-protein helps the SARS-CoV-2 to enter the host cells through the angiotensin-converting enzyme 2 (ACE2). Since ACE2 is required for the binding of SARS-CoV-2 on the host cells, ACE2 inhibitors and blockers have got wider attention, in addition to S-protein and Mpro modulators as potential therapeutics for COVID-19. So far, no specific drugs have shown promising therapeutic potential against COVID-19. The current study was undertaken to evaluate the therapeutic potential of traditional medicinal plants against COVID-19. The bioactives from the medicinal plants, along with standard drugs, were screened for their binding against S-protein, Mpro and ACE2 targets using molecular docking followed by molecular dynamics. Based on the higher binding affinity compared with standard drugs, bioactives were selected and further analyzed for their pharmacological properties such as drug-likeness, ADME/T-test, biological activities using in silico tools. The binding energies of several bioactives analyzed with target proteins were relatively comparable and even better than the standard drugs. Based on Lipinski factors and lower binding energies, seven bioactives were further analyzed for their pharmacological and biological characteristics. The selected bioactives were found to have lower toxicity with a higher GI absorption rate and potent anti-inflammatory and anti-viral activities against targets of COVID-19. Therefore, the bioactives from these medicinal plants can be further developed as phytopharmaceuticals for the effective treatment of COVID-19.Communicated by Ramaswamy H. Sarma.
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Tratamiento Farmacológico de COVID-19 , Plantas Medicinales , Antivirales/química , Antivirales/farmacología , Simulación del Acoplamiento Molecular , Pandemias , SARS-CoV-2RESUMEN
Adipocyte-derived leptin activates multiple oncogenic signaling, leading to breast cancer cell progression and metastasis. Hence, finding effective strategies to inhibit the oncogenic effects of leptin would provide a novel approach for disrupting obesity-associated breast cancer. In the current study, we explored the role of piperine, a major plant alkaloid from Piper nigrum (black pepper), against leptin-induced breast cancer. Piperine treatment significantly inhibited leptin-induced breast cancer cell proliferation, colony formation, migration, and invasion. We found that piperine downregulated the expression of PPARα, a predicted target of miR-181c-3p. Mechanistically, piperine potentiates miR-181c-3p-mediated anticancer potential in leptin-induced breast cancer cells. Interestingly, the knockdown of PPARα reduced the proliferative potential of leptin-induced breast cancer cells. Further, oral administration of piperine inhibited breast tumor growth in diet-induced obese mice, accompanied by the upregulation of miR-181c-3p and downregulation of PPARα expression. Together, piperine represents a potential candidate for further development as an anticancer agent for treating obesity-associated breast cancer.
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Alcaloides , Neoplasias de la Mama , MicroARNs , Animales , Benzodioxoles , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Dieta , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , MicroARNs/genética , Obesidad/tratamiento farmacológico , Obesidad/genética , PPAR alfa/genética , Piperidinas , Alcamidas PoliinsaturadasRESUMEN
Aim: The current investigation is focused on the targeted delivery of doxorubicin through CD44 aptamer-mediated active targeting to the human breast cancer cells. Methods: CD44 aptamer-doxorubicin (Apt-Dox) conjugates were developed by incubating different molar ratios of aptamer and doxorubicin. Cytotoxicity, selective intracellular accumulation and uptake of the Apt-Dox conjugates were analyzed to evaluate the efficacy of Apt-Dox conjugates. Results: Dox was efficiently conjugated with aptamer at 1:2 Apt-Dox molar ratios. Apt-Dox conjugate significantly inhibited the proliferation of CD44-overexpressing breast cancer cells, whereas negligible inhibition of cell proliferation was found in the control cells. Apt-Dox conjugate selectively internalized and accumulated in CD44-overexpressing cells. Conclusion: Apt-Dox conjugate selectively delivers doxorubicin to CD44-expressing cancer cells, thereby inhibiting selective cell proliferation and enhancing the targeted therapy.
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Doxorrubicina , Neoplasias , Humanos , Receptores de HialuranosRESUMEN
BACKGROUND: Breast tumors enriched with breast cancer stem cells (BCSCs), play a crucial role in metastasis and tumor relapse. Hence, targeting BCSCs may lead to efficacious breast cancer therapy. BCSCs have a unique expression of stemness markers, including Nanog, POU5F1, SOX2, and CD44, which play a vital role in cancer stem cell properties. However, the regulation of microRNAs (miRNAs)-mediated cancer stem cell marker expressions is largely unclear. METHODS: MIENTURNET was used to predict miRNA-target interactions. miR-TV, UALCAN and GEPIA databases were used to analyze the expression of miR-145-5p and SOX2. Survival analysis was obtained by cBioportal, KM plotter and Breast Cancer Gene-Expression Miner. RNAComposer was used to perform miRNA-mRNA duplex prediction. In vitro mRNA and miRNA analysis was performed by qRT-PCR. RESULTS: It was observed that miR-145-5p was the common miRNA targeting stemness markers. miR-145-5p expression was found to be lower in breast cancer patients compared to healthy subjects. Based on survival analysis, low expression of miR-145-5p and high expression of SOX2 led to a poor overall survival rate in breast cancer patients. Pathway enrichment analysis indicated that SOX2 was highly enriched with transcription factors. Moreover, SOX2 expression level was also upregulated in axillary metastatic lymph nodules. Further, in vitro ectopic expression of miR-145-5p by its mimic downregulated the SOX2 expression compared to the control mimic. Overall, SOX2 was a direct target for miR-145-5p as per the binding and minimal-free energy. CONCLUSIONS: In this study, miR-145-5p targeting SOX2 was identified as a potential predictive biomarker for breast cancer stemness.
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Neoplasias de la Mama , MicroARNs , Biomarcadores , Neoplasias de la Mama/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
BACKGROUND: Identification and repurposing of therapeutic and preventive strategies against COVID-19 are rapidly undergoing. Several medicinal plants from the Himalayan region have been traditionally used to treat various human disorders. Thus, in our current study, we intended to explore the potential ability of Himalayan medicinal plant (HMP) bioactives against COVID-19 using computational investigations. METHODS: Molecular docking was performed against six crucial targets involved in the replication and transmission of SARS-CoV-2. About forty-two HMP bioactives were analyzed against these targets for their binding energy, molecular interactions, inhibition constant, and biological pathway enrichment analysis. Pharmacological properties and potential biological functions of HMP bioactives were predicted using the ADMETlab and PASS webserver respectively. RESULTS: Our current investigation has demonstrated that the bioactives of HMPs potentially act against COVID-19. Docking results showed that several HMP bioactives had a superior binding affinity with SARS-CoV-2 essential targets like 3CLpro, PLpro, RdRp, helicase, spike protein, and human ACE2. Based on the binding energies, several bioactives were selected and analyzed for pathway enrichment studies. We have found that selected HMP bioactives may have a role in regulating immune and apoptotic pathways. Furthermore, these selected HMP bioactives have shown lower toxicity with pleiotropic biological activities, including anti-viral activities in predicting activity spectra for substances. CONCLUSIONS: Current study results can explore the possibility of HMPs as therapeutic agents against COVID-19.
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COVID-19 , Plantas Medicinales , Humanos , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , SARS-CoV-2RESUMEN
Overexpression of drug efflux transporters is commonly associated with multidrug-resistance in cancer therapy. Here for the first time, we investigated the ability of diindolylmethane (DIM), a dietary bioactive rich in cruciferous vegetables, in enhancing the efficacy of Centchroman (CC) by modulating the drug efflux transporters in human breast cancer cells. CC is a selective estrogen receptor modulator, having promising therapeutic efficacy against breast cancer. The combination of DIM and CC synergistically inhibited cell proliferation and induced apoptosis in breast cancer cells. This novel combination has also hindered the stemness of human breast cancer cells. Molecular docking analysis revealed that DIM had shown a strong binding affinity with the substrate-binding sites of ABCB1 (P-gp) and ABCC1 (MRP1) drug-efflux transporters. DIM has increased the intracellular accumulation of Hoechst and Calcein, the substrates of P-gp and MRP1, respectively, in breast cancer cells. Further, DIM stimulates P-gp ATPase activity, which indicates that DIM binds at the substrate-binding domain of P-gp, and thereby inhibits its efflux activity. Intriguingly, DIM enhanced the intracellular concentration of CC by inhibiting the P-gp and MRP1 expression as well as activity. The intracellular retaining of CC has increased its efficacy against breast cancer. Overall, DIM, a dietary bioactive, enhances the anticancer efficiency of CC through modulation of drug efflux ABC-transporters in breast cancer cells. Therefore, DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy against human breast cancer.
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Antineoplásicos/farmacología , Centcromano/farmacología , Indoles/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/metabolismo , Sitios de Unión , Transporte Biológico/efectos de los fármacos , Línea Celular Tumoral , Centcromano/metabolismo , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Paclitaxel/química , Paclitaxel/farmacología , Unión Proteica , Verapamilo/química , Verapamilo/farmacologíaRESUMEN
BACKGROUND: Coronavirus disease-2019 (COVID-19) is an infectious pandemic caused by SARS-CoV-2. SARS-CoV-2 main protease (Mpro) and spike protein are crucial for viral replication and transmission. Spike protein recognizes the human ACE2 receptor and transmits SARS-CoV-2 into the human body. Thus, Mpro, spike protein, and ACE2 receptor act as appropriate targets for the development of therapeutics against SARS-CoV-2. Spices are traditionally known to have anti-viral and immune-boosting activities. Therefore, we investigated the possible use of selected spice bioactives against the potential targets of SARS-CoV-2 using computational analysis. METHODS: Molecular docking analysis was performed to analyze the binding efficiency of spice bioactives against SARS-CoV-2 target proteins along with the standard drugs. Drug-likeness properties of selected spice bioactives were investigated using Lipinski's rule of five and the SWISSADME database. Pharmacological properties such as ADME/T, biological functions, and toxicity were analyzed using ADMETlab, PASS-prediction, and ProTox-II servers, respectively. RESULTS: Out of forty-six spice bioactives screened, six bioactives have shown relatively better binding energies than the standard drugs and have a higher binding affinity with at least more than two targets of SARS-CoV-2. The selected bioactives were analyzed for their binding similarities with the standard drug, remdesivir, towards the targets of SARS-CoV-2. Selected spice bioactives have shown potential drug-likeness properties, with higher GI absorption rate, lower toxicity with pleiotropic biological roles. CONCLUSIONS: Spice bioactives have the potential to bind with the specific targets involved in SARS-CoV-2 infection and transmission. Therefore, spice-based nutraceuticals can be developed for the prevention and treatment of COVID-19.
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Antivirales/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , SARS-CoV-2/química , Especias , Proteínas Virales , Bases de Datos de Proteínas , Humanos , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/químicaRESUMEN
BACKGROUND: Lung cancer is the leading cause of cancer-associated death worldwide with limited treatment options. The major available treatment options are surgery, radiotherapy, chemotherapy and combinations of these treatments. In chemotherapy, tyrosine kinase inhibitors and taxol are the first lines of chemotherapeutics used for the treatment of lung cancer. Often drug resistance in the clinical settings hinders the efficiency of the treatment and intrigues the tumor relapse. Drug-resistance is triggered either by intrinsic factors or due to the prolonged cycles of chemotherapy as an acquired-resistance. There is an emerging role of non-coding RNAs (ncRNAs), including notorious microRNAs (miRNAs), proposed to be actively involved in the regulations of various tumor-suppressor genes and oncogenes. RESULTS: The altered gene expression by miRNA is largely mediated either by the degradation or by interfering with the translation of targeted mRNA. Unlike miRNA, other type of ncRNAs, such as long non-coding RNAs (lncRNAs), can target the transcriptional activator or the repressor, RNA polymerase, and even DNA-duplex to regulate the gene expressions. Many studies have confirmed the crucial role of ncRNAs in lung adenocarcinoma progression and importantly, in the acquisition of chemoresistance. Recently, ncRNAs have become early biomarkers and therapeutic targets for lung cancer. CONCLUSION: Targeting ncRNAs could be an effective approach for the development of novel therapeutics against lung cancer and to overcome the chemoresistance.