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CONTEXT: Multiwalled carbon nanotubes (MWCNTs) functionalized with lysine via 1,3-dipolar cycloaddition and conjugated to galactose or mannose are potential nanocarriers that can effectively bind to the lectin receptor in MDA-MB-231 or MCF-7 breast cancer cells. In this work, a method based on molecular dynamics (MD) simulation was used to predict the interaction of these functionalized MWCNTs with doxorubicin and obtain structural evidence that allows a better understanding of the drug loading and release process. The MD simulations showed that while doxorubicin only interacted with pristine MWCNTs through π-π stacking interactions, functionalized MWCNTs were also able to establish hydrogen bonds, suggesting that the functionalized groups improve doxorubicin loading. Moreover, the elevated adsorption levels observed for functionalized nanotubes further support this enhancement in loading efficiency. MD simulations also shed light on the intratumoral pH-specific release of doxorubicin from functionalized MWCNTs, which is induced by protonation of the daunosamine moiety. The simulations show that this change in protonation leads to a lower absorption of doxorubicin to the MWCNTs. The MD studies were then experimentally validated, where functionalized MWCNTs showed improved dispersion in aqueous medium compared to pristine MWCNTs and, in agreement with the computational predictions, increased drug loading capacity. Doxorubicin-loaded functionalized MWCNTs demonstrated specific release of doxorubicin in tumor microenvironment (pH = 5.0) with negligible release in the physiological pH (pH = 7.4). Furthermore, doxorubicin-free MWNCT nanoformulations exhibited insignificant cytotoxicity. The experimental studies yielded nearly identical results to the MD studies, underlining the usefulness of the method. Our functionalized MWCNTs represent promising non-toxic nanoplatforms with enhanced aqueous dispersibility and the potential for conjugation with ligands for targeted delivery of anti-cancer drugs to breast cancer cells. METHODS: The computational model of a pristine carbon nanotube was created with the buildCstruct 1.2 Python script. The lysinated functionalized groups were added with PyMOL and VMD. The carbon nanotubes and doxorubicin molecules were parameterized using the general AMBER force field, and RESP charges were determined using Gaussian 09. Molecular dynamics simulations were carried out with the AMBER 20 software package. Adsorption levels were calculated using the water-shell function of cpptraj. Cytotoxicity was evaluated via a MTT assay using MDA-MB-231 and MCF-7 breast cancer cells. Drug uptake of doxorubicin and doxorubicin-loaded MWCNTs was measured by fluorescence microscopy.
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Doxorrubicina , Simulación de Dinámica Molecular , Nanotubos de Carbono , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Nanotubos de Carbono/química , Humanos , Lisina/química , Portadores de Fármacos/química , Células MCF-7 , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Línea Celular Tumoral , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificaciónRESUMEN
Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/ß-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/ß-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the ß-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.
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Apoptosis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Neoplasias de la Boca , Nanopartículas , Células Madre Neoplásicas , Resveratrol , Proteína p53 Supresora de Tumor , Proteína con Dedos de Zinc GLI1 , beta Catenina , Apoptosis/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Resveratrol/farmacología , Proteína con Dedos de Zinc GLI1/metabolismo , Proteína con Dedos de Zinc GLI1/genética , beta Catenina/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Ratones , Línea Celular Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer cells merely exist in isolation; rather, they exist in an intricate microenvironment composed of blood vessels, signalling molecules, immune cells, stroma, fibroblasts, and the ECM. The TME provides a setting that is favourable for the successful growth and survivance of tumors. Angiogenesis is a multifaceted process that is essential for the growth, invasion, and metastasis of tumors. TME can be visualized as a "concert hall," where various cellular and non-cellular factors perform in a "symphony" to orchestrate tumor angiogenesis and create "Havoc" instead of "Harmony". In this review, we comprehensively summarized the involvement of TME in regulating tumor angiogenesis. Especially, we have focused on immune cells and their secreted factors, inflammatory cytokines and chemokines, and their role in altering the TME. We have also deciphered the crosstalk among various cell types that further aids the process of tumor angiogenesis. Additionally, we have highlighted the limitations of existing anti-angiogenic therapy and discussed various potential strategies that could be used to overcome these challenges and improve the efficacy of anti-angiogenic therapy.
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Neoplasias , Neovascularización Patológica , Microambiente Tumoral , Humanos , Neovascularización Patológica/patología , Neoplasias/patología , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Animales , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , AngiogénesisRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with a survival rate of <5 years. The TGF-ß plays a significant role in the progression and severity of IPF. The TGF-ß receptor type1 TGFBR1 antagonists inhibit the process of fibrosis and may have a role in the treatment of IPF. The main objective of the study was to identify promising drug candidates against IPF using In-silico and In-vitro evaluation methods. An in-silico screening was carried out of the marketed Coxibs to find their TGFBR1 inhibitory potential considering their structural resemblance with the JZO-a co-crystalized ligand of the crystal structure of the TGFBR1. The virtual screening yielded rofecoxib as a TGFBR1 ligand with a significant docking score. To further validate the outcome of molecular docking studies, MD simulation of 200 ns was carried out followed by the determination of conformational stability, binding free energy calculation using MMPBSA/MMGBSA, and Free Energy Landscape (FEL). The therapeutic efficacy of rofecoxib was compared with that of nintedanib (a therapeutic agent used in the treatment of IPF) at equimolar concentrations (5 µM). The model of TGF-ß1 (1 ng/ml)-induced EMT of A549 was used to determine the effect of rofecoxib on the EMT markers like cellular morphology, cytokine expressions, fibrosis associated protein, E-cadherin, and α-smooth muscle actin. In vitro results indicated that rofecoxib significantly suppresses the TGF-ß1-induced EMT of A549 cells and validates the possible preventive/protective role of rofecoxib in pulmonary fibrosis. In conclusion, rofecoxib may be considered for repositioning as an anti-fibrotic agent.Communicated by Ramaswamy H. Sarma.
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Cancer stem cells (CSCs) exhibit intricate regulatory dynamics within the tumor microenvironment, involving interactions with various components like mesenchymal stem cells (MSCs), adipocytes, cancer-associated fibroblasts (CAFs), endothelial cells, tumor-associated macrophages (TAMs), and other immune cells. These interactions occur through complex networks of cytokines, inflammatory factors, and several growth factors. Diverse techniques are employed to generate CSCs, including serum-free sphere culture, chemotherapy, and radiation therapy. A novel approach to generate CSCs involves co-culturing, wherein recent research highlights the role of secreted factors such as inflammatory cytokines from MSCs, CAFs, and TAMs in inducing CSC-like characteristics in cancer cells. While the co-culture method shows promise in generating CSCs, further investigations are needed to comprehensively establish this process. This chapter focuses on establishing a co-culture-based technique for generating CSCs by combining cancer cells with TAMs and CAFs, elucidating the intricate mechanisms underlying this phenomenon.
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Fibroblastos Asociados al Cáncer , Neoplasias , Técnicas de Cocultivo , Células Endoteliales , Citocinas/metabolismo , Fibroblastos Asociados al Cáncer/patología , Células Madre Neoplásicas/metabolismo , Microambiente Tumoral , Línea Celular Tumoral , Neoplasias/patologíaRESUMEN
It is a well-known fact that cancer can be augmented by infections and inflammation. In fact, chronic inflammation establishes a tumor-supporting-microenvironment (TME), which contributes to neoplastic progression. Presently, extensive research is going on to establish the interrelationship between infection, inflammation, immune response, and cancer. Cytokines are the most essential components in this linkage, which are secreted by immune cells and stromal cells of TME. Cytokines have potential involvement in tumor initiation, elongation, progression, metastatic outgrowth, angiogenesis, and development of therapeutic resistance. They are also linked with increased cancer symptoms along with reduced quality of life in advanced cancer patients. The cancer patients experience multiple symptoms including pain, asthenia, fatigue, anorexia, cachexia, and neurodegenerative disorders etc. Anti-cancer therapeutics can be developed by targeting cytokines along with TME to reduce the immunocompromised state and also modulate the TME. This review article depicts the composition and function of different inflammatory cells within the TME, more precisely the role of cytokines in cancer initiation, elongation, and progression as well as the clinical effects in advanced cancer patients. It also provides an overview of different natural compounds, nanoparticles, and chemotherapeutic agents that can target cytokines along with TME, which finally pave the way for cytokines-targeted anti-cancer therapeutics.
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Citocinas , Neoplasias , Humanos , Calidad de Vida , Neoplasias/tratamiento farmacológico , Transformación Celular Neoplásica , Inflamación , Microambiente TumoralRESUMEN
Most human malignancies are attributed to exposure to infectious organisms such as viruses. Certain infections that can induce cancer can evade the immune system, leading to persistent inflammation that facilitates uncontrolled cell growth. Moreover, these pathogens can increase the likelihood of oncogenic transformation, leading to cancer development. Despite significant advancements in medicine, oncological research continues to seek innovative treatment techniques in light of the constraints imposed by traditional therapeutic agents. Virus-based therapy is a novel treatment method that has garnered significant interest due to its broad range of applications. Virotherapy employs oncolytic viruses that are genetically modified to target tumor cells specifically, undergo replication inside them and destroy the malignant cells. Additionally, this therapeutic approach elicits an anticancer response by boosting the patient's immune system. In addition, viruses are commonly employed as targeted delivery vectors for the precise transportation of various genes, medicinal compounds and immune-stimulating substances. Furthermore, virotherapy offers more excellent anticancer activity in combination with established treatment modalities such as immune therapy, chemotherapy and radiation therapy. This review presents a concise overview of the roles played by infectious agents, such as viruses in cancer progression. In addition, we have thoroughly summarized the advancements in utilizing viruses for their oncolytic properties in conjunction with established cancer treatment modalities such as chemotherapy, radiation and immunotherapy.
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Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Viroterapia Oncolítica/métodos , Neoplasias/terapia , Neoplasias/patología , Inmunoterapia/métodosRESUMEN
Recently, we reported that a combination of a natural, bioactive compound Resveratrol (RES) and a PARP inhibitor Olaparib (OLA) deregulated the homologous recombination (HR) pathway, and enhanced apoptosis in BRCA1-wild-type, HR-proficient breast cancer cells. Upon DNA damage, chromatin relaxation takes place, which allows the DNA repair proteins to access the DNA lesion. But whether chromatin remodeling has any role in RES + OLA-mediated HR inhibition is not known. By using in vitro and ex vivo model systems of breast cancer, we have investigated whether RES + OLA inhibits chromatin relaxation and thereby blocks the HR pathway. It was found that RES + OLA inhibited PARP1 activity, terminated PARP1-BRCA1 interaction, and deregulated the HR pathway only in the chromatin fraction of MCF-7 cells. DR-GFP reporter plasmid-based HR assay demonstrated marked reduction in HR efficiency in I-SceI endonuclease-transfected cells treated with OLA. RES + OLA efficiently trapped PARP1 at the DNA damage site in the chromatin of MCF-7 cells. Unaltered expressions of HR proteins were found in the chromatin of PARP1-silenced MCF-7 cells, which confirmed that RES + OLA-mediated DNA damage response was PARP1-dependent. Histone Acetyltransferase (HAT) activity and histone H4 acetylation assays showed reduction in HAT activity and H4 acetylation in RES + OLA-treated chromatin fraction of cells. Western blot analysis showed that the HAT enzyme TIP60, P400 and acetylated H4 were downregulated after RES + OLA exposure. In the co-immunoprecipitation assay, it was observed that RES + OLA caused abolition of PARP1-TIP60-BRCA1 interaction, which suggested the PARP1-dependent TIP60-BRCA1 association. Unaltered expressions of PAR, BRCA1, P400, and acetylated H4 in the chromatin of TIP60-silenced MCF-7 cells further confirmed the role of TIP60 in PARP1-mediated HR activation in the chromatin. Similar results were obtained in ex vivo patient-derived primary breast cancer cells. Thus, the present study revealed that RES + OLA treatment inhibited PARP1 activity in the chromatin, and blocked TIP60-mediated chromatin relaxation, which, in turn, affected PARP1-dependent TIP60-BRCA1 association, resulting in deregulation of HR pathway in breast cancer cells.
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Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Cromatina , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Resveratrol/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Reparación del ADN por RecombinaciónRESUMEN
Tumor associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment secrete several cytokines, which involved in tumor initiation, progression, metastatic outgrowth and angiogenesis. However, the association between TAMs and CAFs in the context of tumor development remain unclear. Here, we studied the relationship between TAMs and CAFs along with the involvement of cytokines in the production of cancer-stem-like-cells (CSCs) in oral cancer cells and explored the potential anticancer effects of Nano-formulated Resveratrol (Res-NP) using an activated macrophage-M1 (AM-M1) and activated fibroblast cells as the model system. IL-6 secretion was found to be enhanced in the conditioned-medium (CM) when AM-M1 cells + CAFs-like cells were cocultured together. CSCs-enriched population was developed after addition of CM of AM-M1 +CAFs in H-357 cells and patient-derived-primary-oral-cancer cells. AM-M1 cells+ CAFs-like cells secreted IL-6 enhanced CSCs growth, proliferation, metastasis, and angiogenesis. IL-6 was found to promote PD-L1 expression in CSCs-enriched cells via JAK2/STAT3 pathway, as evident from the enhanced expression of p-JAK2 and p-STAT3. Nevertheless, Res-NP inhibited CSCs proliferation and reduced the expression of metastatic and angiogenic markers, in ovo blood vascularization, NO production and MMPs expression. Res-NP delinked the association between AM-M1 and CAFs by blocking IL-6 production and also disrupted the potential connection between IL-6 and PD-L1 with considerable decrease in p-JAK2 and p-STAT3 expressions. IL-6 depletion inhibited stemness and angiogenesis in oral CSCs by downregulating PD-L1 via JAK2/STAT3 cascade. Similar observations were also observed in Res-NP treated xenograft mice. Thus, data demonstrate that CSCs growth is dependent on IL-6/PD-L1 axis. Res-NP deregulates the association between AM-M1 and CAFs along-with attenuates carcinogenesis in in vitro, in ovo, ex vivo and in vivo model systems by inhibiting PD-L1 via IL-6/JAK2/STAT3 axis.
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Fibroblastos Asociados al Cáncer , Neoplasias de la Boca , Humanos , Animales , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Interleucina-6/metabolismo , Resveratrol/farmacología , Macrófagos Asociados a Tumores/metabolismo , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Neoplasias de la Boca/metabolismo , Microambiente Tumoral , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Aim: This study aimed to determine if quinacrine-gold hybrid nanoparticles (QAuNPs) + near-infrared (NIR) deregulate HSP-70/P300 complex-mediated H3K14 acetylation in estrogen receptor/progesterone receptor (ER/PR+) breast cancer stem cells (CSCs). Materials & methods: Various cells and mouse-based systems were used as models. Results: QAuNP + NIR treatment reduced the nuclear translocation of HSP-70, affected the histone acetyltransferase activity of P300 and specifically decreased H3K14 acetylation in ER/PR+ breast CSCs. Finally, HSP-70 knockdown showed a reduction in P300 histone acetyltransferase activity, decreased H3K14 acetylation and inhibited activation of the TGF-ß gene. Conclusion: This study revealed that QAuNP + NIR irradiation inhibits oncogenic activation of the TGF-ß gene by decreasing H3K14 acetylation mediated through the HSP-70/P300 nuclear complex in ER/PR+ breast CSCs.
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Nanopartículas , Neoplasias , Animales , Ratones , Acetilación , Oro , Histona Acetiltransferasas , Células Madre Neoplásicas , Quinacrina/farmacología , Factor de Crecimiento Transformador beta , Humanos , FemeninoRESUMEN
Extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae infection is a serious global threat. ESBLs target 3rd generation cephalosporin antibiotics, the most commonly prescribed medicine for gram-negative bacterial infections. As bacteria are prone to develop resistance against market-available ESBL inhibitors, finding a novel and effective inhibitor has become mandatory. Among ESBL, the worldwide reported two enzymes, CTX-M-15 and CTX-M-3, are selected for the present study. CTX-M-3 protein was modeled, and two thousand phyto-compounds were virtually screened against both proteins. After filtering through docking and pharmacokinetic properties, four phyto-compounds (catechin gallate, silibinin, luteolin, uvaol) were further selected for intermolecular contact analysis and molecular dynamics (MD) simulation. MD trajectory analysis results were compared, revealing that both catechin gallate and silibinin had a stabilizing effect against both proteins. Silibinin having the lowest docking score, also displayed the lowest MIC (128 µg/mL) against the bacterial strains. Silibinin was also reported to have synergistic activity with cefotaxime and proved to have bactericidal effect. Nitrocefin assay confirmed that silibinin could inhibit beta-lactamase enzyme only in living cells, unlike clavulanic acid. Thus the present study validated the CTX-M inhibitory activity of silibinin both in silico and in vitro and suggested its promotion for further studies as a potential lead. The present study adopted a protocol through the culmination of bioinformatics and microbiological analyses, which will help future researchers identify more potential leads and design new effective drugs.Communicated by Ramaswamy H. Sarma.
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Antibacterianos , Enterobacteriaceae , Silibina/farmacología , Antibacterianos/farmacología , Enterobacteriaceae/metabolismo , Cefotaxima/farmacología , beta-Lactamasas/metabolismo , Pruebas de Sensibilidad MicrobianaRESUMEN
The presence of cancer stem cells (CSCs) in the tumor microenvironment (TME) is majorly responsible for the development and recurrence of cancer. Earlier reports suggested that upon DNA damage, poly-(ADP-ribose) polymerase-1 (PARP-1) helps in chromatin modulation and DNA repair process, thereby promoting CSC survival. But whether a combination of DNA damaging agents along with PARP inhibitors can modulate chromatin assembly, inhibit DNA repair processes, and subsequently target CSCs is not known. Hence, we have investigated the effect of nontoxic bioactive compound quinacrine (QC) and a potent PARP inhibitor Talazoparib in patient-derived oral mucosa CSCs (OM-CSCs) and in vivo xenograft mice preclinical model systems. Data showed that QC + Talazoparib inhibited the PARP-1-mediated chromatin remodelers' recruitment and deregulated HAT activity of GCN5 (general control nonderepressible-5) and P300 at DNA damage site, thereby preventing the access of repair proteins to the damaged DNA. Additionally, this combination treatment inhibited topoisomerase activity, induced topological stress, and induced apoptosis in OM-CSCs. Similar results were observed in an in vivo xenograft mice model system. Collectively, the data suggested that QC + Talazoparib treatment inhibited BER pathway, induced genomic instability and triggered apoptosis in OM-CSCs through the deregulation of PARP-1-mediated chromatin remodelers (GCN5 and P300) activity. Schematic representation of QC + Talazoparib-induced apoptosis in oral mucosa CSCs. (1) Induction of DNA damage takes place after QC treatment (2) PARP1-mediated PARylation at the site of DNA damage, which recruits multiple chromatin remodelers (3) Acetylation at the histone tails relax the structure of chromatin and recruits the BER pathway proteins at the site of DNA damage. (4) BER pathway activated at the site of DNA damage. (5) CSCs survive after successful repair of DNA damage. (6) Treatment of QC-treated CSCs with PARP inhibitor Talazoparib (7) Inhibition of PARylation results in failure of chromatin remodelers to interact with PARP1. (8) Inhibition of acetylation status leads to chromatin compaction. (9) BER pathway proteins are not recruited at the site of DNA damage, resulting in inhibition of BER pathway and accumulation of unrepaired DNA damage, leading to apoptosis and cell death.
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Antineoplásicos , Quinacrina , Humanos , Animales , Ratones , Quinacrina/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Mucosa Bucal , Reparación del ADN , Antineoplásicos/farmacología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Daño del ADN , Cromatina , ADN/farmacología , ApoptosisRESUMEN
OBJECTIVE: Sensitization of mismatch repair (MMR)-deficient colorectal cancer (CRC) cells by 5-Fluorouracil (5-FU) is well-documented. But not much is known about the treatment of MMR-proficient CRC cancer stem cells (CRC-CSCs). Here, we investigated whether a PARP inhibitor (ABT-888) can enhance the 5-FU-mediated apoptosis in CRC-CSCs through MMR pathway inhibition. METHODS: The anti-cancer action of 5-FU+ABT-888 combination in CRC-CSCs has been studied by using in vitro, ex vivo, and in vivo preclinical model systems. RESULTS: 5-FU caused DNA damage in CRC-CSCs, and ABT-888 enhanced the accumulation of DNA mismatches by downregulating the MMR pathway, triggering S-phase arrest, and finally apoptosis and cell death in 5-FU-pre-treated MMR-proficient-CRC-CSCs at much lower concentrations than their individual treatments. After 5-FU treatment, PARylated-PARP1 activated MMR pathway by interacting with MSH6. But, upon ABT-888 treatment in 5-FU-pre-exposed CSCs, PARylation was inhibited, as a result of which PARP1 could not interact with MSH6, and other MMR proteins were downregulated. The role of MSH6 in PARP1-mediated MMR activation, was confirmed by silencing MSH6 gene, which resulted in MMR pathway shutdown. Similar results were obtained in ex vivo and in vivo model systems. CONCLUSIONS: 5-FU+ABT-888 combination enhanced CRC-CSCs death by increasing DNA damage accumulation and simultaneously inhibiting the MMR pathway in MMR-proficient cells. But this study does not discuss whether the combination treatment will increase the sensitivity of MMR-deficient CSCs, for which further research will be performed in the future.
5-FU is a well-known drug commonly used to treat colorectal cancer and it causes DNA damage inside the cancer cells. The limitation of 5-FU treatment is the development of chemoresistance due to the high DNA repair capacity of cancer stem cells present in the tumor microenvironment. In this study, a novel chemotherapeutic approach has been developed to target colorectal cancer stem cells by using a combination of 5-FU and a PARP1 inhibitor (ABT-888). Here, 5-FU caused DNA damage and ABT-888 enhanced the accumulation of the DNA lesions by inhibiting the MMR repair pathway in 5-FU-pre-treated MMR-proficient-CRC-CSCs. This resulted in S-phase arrest, induction of apoptosis, and finally CSCs death.
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Antineoplásicos , Neoplasias Colorrectales , Humanos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN , Células Madre NeoplásicasRESUMEN
BACKGROUND: Breast cancer stem cells (BCSCs) have a critical role in progression of breast cancer by inducing angiogenesis. Several therapeutic strategies have been designed for the treatment of breast cancer by specifically preventing angiogenesis. But there is a dearth of study regarding the treatment procedure which can specifically target and kill the BCSCs and cause lesser harm to healthy cells of the body. A plant-based bioactive compound Quinacrine (QC) specifically kills cancer stem cells (CSCs) without harming healthy cells and also inhibits cancer angiogenesis but the detailed mechanistic study of its anti-CSCs and anti-angiogenic activity is yet to explore. HYPOTHESIS: Earlier report showed that both cMET and ABCG2 play an essential role in cancer angiogenesis. Both are present on the cell surface of CSCs and share an identical ATP-binding domain. Interestingly, QC a plant based and bioactive compound which was found to inhibit the function of CSCs marker cMET and ABCG2. These relevant evidence led us to hypothesize that cMET and ABCG2 may interact with each other and induce the production of angiogenic factors, resulting in activation of cancer angiogenesis and QC might disrupt the interaction between them to stop this phenomena. METHODS: Co-immunoprecipitation assay, immunofluorescence assay, and western blotting were performed by using ex vivo patient-derived breast cancer-stem-cells (PDBCSCs) and human umbilical vein endothelial cells (HUVECs). In silico study was carried out to check the interaction between cMET and ABCG2 in presence or absence of QC. Tube formation assay using HUVECs and in ovo Chorioallantoic membrane (CAM) assay using chick fertilized eggs were performed to monitor angiogenesis. In vivo patient-derived xenograft (PDX) mice model was used to validate in silico and ex vivo results. RESULTS: Data revealed that in a hypoxic tumor microenvironment (TME), cMET and ABCG2 interact with each other and upregulate HIF-1α/VEGF-A axis to induce breast cancer angiogenesis. In silico and ex vivo study showed that QC disrupted the interaction between cMET and ABCG2 to inhibit the angiogenic response in endothelial cells by reducing the secretion of VEGF-A from PDBCSCs within the TME. Knockdown of cMET, ABCG2 or both, significantly downregulated the expression of HIF-1α and reduced the secretion of pro-angiogenic factor VEGF-A in the TME of PDBCSCs. Additionally, when PDBCSCs were treated with QC, similar experimental results were obtained. CONCLUSION: In silico, in ovo, ex vivo and in vivo data confirmed that QC inhibited the HIF-1α/VEGF-A mediated angiogenesis in breast cancer by disrupting the interaction between cMET and ABCG2.
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Neoplasias de la Mama , Quinacrina , Humanos , Animales , Ratones , Femenino , Quinacrina/farmacología , Quinacrina/metabolismo , Quinacrina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de la Mama/patología , Células Endoteliales/metabolismo , Células Madre Neoplásicas/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Línea Celular Tumoral , Microambiente Tumoral , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas de Neoplasias/metabolismoRESUMEN
A trans-membrane receptor tyrosine kinase, cMET, belonging to the MET proto-oncogene family, is responsible for cancer metastasis and angiogenesis. But not much is known about the role of cMET in growth and progression of cancer stem cells (CSCs). Earlier studies have shown that Quinacrine (QC), a bioactive agent, has anti-CSCs activity. Here, the role of QC in deregulation of cMET-mediated metastasis and angiogenesis has been systematically evaluated in vitro in highly metastatic breast CSCs (mBCSCs), ex vivo in patient-derived breast cancer stem cells (PDBCSCs) and in vivo in xenograft mice model systems. Cell proliferation, migration, invasion and representative metastasis markers were upregulated in cMET-overexpressed cells and QC exposure inhibited these processes in both mBCSCs and PDBCSCs. Interestingly, metastasis was significantly inhibited by QC in cMET-overexpressed cells but comparatively lesser significant alteration of the process was noted in cMET-silenced cells. Increase in vascularization (in in ovo CAM assay), and cell-cell tube formation (in HUVECs), and enhanced MMP9 and MMP2 enzymatic activities (in gelatin zymography) were noted after cMET overexpression but these processes got reversed after cMET knockdown or QC treatment in cMET-overexpressed cells. QC inhibited angiogenesis significantly in cMET-overexpressed cells, but lesser significant change was observed in cMET-silenced cells. Reduction in tumor volume and decreased expression of metastatic and angiogenic markers were also noted in xenograft mice after QC treatment. Furthermore, QC inhibited cMET activity by dephosphorylation of its tyrosine residues (Y1234 and Y1356) and downregulation of its downstream cascade. Thus, QC inhibited the cMET-mediated metastasis and angiogenesis in in vitro, in ovo, in vivo and ex vivo model systems. Ligand (HGF) binding leads to receptor dimerization and phosphorylation of tyrosine kinase domain of cMET. This activates the cMET signaling cascade. The representative downstream metastasis and angiogenesis-related proteins get upregulated and induce the metastasis and angiogenesis process. But after the QC treatment, cMET get dephosphorylated and inactivated. As a result, the downstream signaling proteins of cMET along with the other representative metastatic and angiogenic factors get downregulated. These lead to inhibition of cMET-mediated metastasis and angiogenesis. (Created with BioRender.com).
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Aim: This study aimed to explore the antiangiogenic mechanism of quinacrine-gold hybrid nanoparticle (QAuNP) and near-infrared (NIR) radiation in patient-derived primary breast cancer stem cells. Materials & methods: Various cell-based in ovo angiogenesis and in vivo patient-derived xenograft mouse systems were used as models for the study. Results: The experimental results showed that QAuNP + NIR treatment deregulated the HSP-70/TGF-ß physical interaction in primary breast cancer stem cells. Reduced TGF-ß secretion in the tumor microenvironment inhibited angiogenesis activation in endothelial cells by deregulating the TGF-ß-mediated PI3K/AKT/mTOR cascade. Conclusion: This study revealed that QAuNP + NIR irradiation downregulated HSP-70 expression, inhibited the HSP-70/TGF-ß interaction, reduced the secretion of TGF-ß in the tumor microenvironment and ultimately inhibited TGF-ß-mediated angiogenesis.
This study discovered that the formation of blood vessels in breast cancer is significantly reduced when hybrid nanoparticles and infrared laser therapy are used to treat breast cancer stem cells. The secretory cytokines in the tumor microenvironment primarily responsible for developing blood vessels in the tumor are dramatically reduced by treatment. As a result, the tumor's blood vessel growth is reduced, making it difficult for the cancer cells to get the nutrients and oxygen they need to survive.
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Neoplasias de la Mama , Nanopartículas , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Células Endoteliales/metabolismo , Oro , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas , Quinacrina/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Espectroscopía Infrarroja Corta , Proteínas HSP70 de Choque Térmico/metabolismoRESUMEN
Viruses have a worldwide impact on healthcare and social and economic growth because they are the largest cause of mortality due to infectious diseases. Furthermore, the long-term conventional drug use comes with substantial risks to public health, such as the rapid evolution of drug resistance and the emergence of secondary side effects. Therefore, it is necessary to develop new methods for the treatment of virus-related diseases. In this case, the use of nanomaterial-based nanomedicines possesses tremendous advantages over the traditional treatment approach. Nanomaterial-based drug delivery systems have unique features that make them promising candidates in the pursuit of therapeutic benefits. In this review, we present the various biocompatible nanomaterials that show promise as nanomedicines for anti-viral therapy. Also, we include how current developments in nanomedicine are being used to treat and prevent the most common viral illnesses such as the flu, HIV, SARS-CoV-2, monkeypox, and human papillomaviruses.
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COVID-19 , Enfermedades Transmisibles , Virosis , Humanos , Nanomedicina/métodos , SARS-CoV-2 , Sistemas de Liberación de Medicamentos/métodos , Virosis/tratamiento farmacológicoRESUMEN
Incorporating single or combined nanofillers in polymeric matrices is a promising approach for developing antimicrobial materials for applications in wound healing and packaging etc. This study reports a facile fabrication of antimicrobial nanocomposite films using biocompatible polymers sodium carboxymethyl cellulose (CMC) and sodium alginate (SA) reinforced with nanosilver (Ag) and graphene oxide (GO) using the solvent casting approach. Eco-friendly synthesis of Ag nanoparticles within a size range of 20-30 nm was carried out within the polymeric solution. GO was introduced into the CMC/SA/Ag solution in different weight percentages. The films were characterized by UV-Vis, FT-IR, Raman, XRD, FE-SEM, EDAX, and TEM. The results indicated the enhanced thermal and mechanical performance of CMC/SA/Ag-GO nanocomposites with increased GO weight %. The antibacterial efficacy of the fabricated films was evaluated on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The CMC/SA/Ag-GO2% nanocomposite exhibited the highest zone of inhibition of 21.30 ± 0.70 mm against E. coli and 18.00 ± 1.00 mm against S. aureus. The CMC/SA/Ag-GO nanocomposites exhibited excellent antibacterial activity as compared to CMC/SA and CMC/SA-Ag due to the synergetic bacterial growth inhibition activities of the GO and Ag. The cytotoxic activity of the prepared nanocomposite films was also assessed to investigate their biocompatibility.
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Nanopartículas del Metal , Nanocompuestos , Staphylococcus aureus , Alginatos/farmacología , Plata/química , Nanopartículas del Metal/química , Carboximetilcelulosa de Sodio/química , Escherichia coli , Espectroscopía Infrarroja por Transformada de Fourier , Antibacterianos/farmacología , Antibacterianos/química , Nanocompuestos/químicaRESUMEN
Cancer patients frequently report experiencing pain as one of their symptoms. Cancerrelated pain is often caused by the tumor itself, especially when the tumor is pressing on nerves. In addition to the pain caused by the tumor itself, patients also experience discomfort from the treatment, such as surgery, chemotherapy, radiation therapy, and the diagnostic procedures. The majority of today's pain therapies rely on opioid analgesics, which have not been shown to be effective. The adverse effects of opioids and their addictive properties call for the development of innovative treatment techniques. Nanotechnology offers answers to the issues raised above, which are related to the utilization of more conventional modes of therapy. These nanotechnology-based nanotherapeutics reduce the systemic toxicity, offering outstanding selectiveness and prolonged release of the analgesic drugs at the target site. Thus, these reduce cancer-induced pain in the patients. In this article, we will explain the mechanism behind the most common types of pain that are caused by cancer, including neuropathic, somatic, and visceral pain. In addition, a comprehensive discussion is held on the use of various nanotherapeutics as analgesic drug carriers, as well as on their impacts and the potential opportunities that lie ahead in the field of cancer pain treatment.
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Neoplasias , Manejo del Dolor , Humanos , Manejo del Dolor/efectos adversos , Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Analgésicos Opioides , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , NanotecnologíaRESUMEN
Wnt, Hedgehog (Hh), and Notch signaling pathways are the evolutionarily conserved signaling pathways that regulate the embryonic development and also play crucial role in maintaining stemness properties of cancer stem cells (CSCs) and inducing epithelial-to-mesenchymal transition (EMT), metastasis, and angiogenesis. It has been highly challenging to inhibit the CSCs growth and proliferation as these are capable of evading chemotherapeutic drugs and cause cancer recurrence through multiple signaling pathways. Therefore, novel therapeutic strategies to target the key players involved in the crosstalk of these signaling pathways need to be developed. In this review, we have identified the interacting molecules of Wnt, Hh, and Notch pathways responsible for enhancing the malignant properties of CSCs. Analyzing the functions of these crosstalk molecules will help us to find an approach toward the development of new anti-cancer drugs for inhibition of CSCs growth and progression. Long non-coding RNAs (LncRNAs) play a significant role in various cellular processes, like chromatin remodeling, epigenetic modifications, transcriptional, and post-transcriptional regulations. Here, we have highlighted the research findings suggesting the involvement of LncRNAs in maintenance of the stemness properties of CSCs through modulation of the above-mentioned signaling pathways. We have also discussed about the different therapeutic approaches targeting those key players responsible for mediating the crosstalk between the pathways. Overall, this review article will surely help the cancer biologists to design novel anti-CSCs agents that will open up a new horizon in the field of anti-cancer therapeutics.