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The rising global burden of cancer has driven considerable efforts into the research and development of effective anti-cancer agents. Fortunately, with impressive advances in transcriptome profiling technology, the Connectivity Map (CMap) database has emerged as a promising and powerful drug repurposing approach. It provides an important platform for systematically discovering of the associations among genes, small-molecule compounds and diseases, and elucidating the mechanism of action of drug, contributing toward efficient anti-cancer pharmacotherapy. Moreover, CMap-based computational drug repurposing is gaining attention because of its potential to overcome the bottleneck constraints faced by traditional drug discovery in terms of cost, time and risk. Herein, we provide a comprehensive review of the applications of drug repurposing for anti-cancer drug discovery and summarize approaches for computational drug repurposing. We focus on the principle of the CMap database and novel CMap-based software/algorithms as well as their progress achieved for drug repurposing in the field of oncotherapy. This article is expected to illuminate the emerging potential of CMap in discovering effective anti-cancer drugs, thereby promoting efficient healthcare for cancer patients.
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Reposicionamiento de Medicamentos , Perfilación de la Expresión Génica , Humanos , Bases de Datos Factuales , Programas Informáticos , AlgoritmosRESUMEN
Dynamic therapies, which induce reactive oxygen species (ROS) production in situ through endogenous and exogenous stimulation, are emerging as attractive options for tumor treatment. However, the complexity of the tumor substantially limits the efficacy of individual stimulus-triggered dynamic therapy. Herein, bimetallic copper and ruthenium (Cu@Ru) core-shell nanoparticles are applied for endo-exogenous stimulation-triggered dynamic therapy. The electronic structure of Cu@Ru is regulated through the ligand effects to improve the adsorption level for small molecules, such as water and oxygen. The core-shell heterojunction interface can rapidly separate electron-hole pairs generated by ultrasound and light stimulation, which initiate reactions with adsorbed small molecules, thus enhancing ROS generation. This synergistically complements tumor treatment together with ROS from endogenous stimulation. In vitro and in vivo experiments demonstrate that Cu@Ru nanoparticles can induce tumor cell apoptosis and ferroptosis through generated ROS. This study provides a new paradigm for endo-exogenous stimulation-based synergistic tumor treatment.
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Apoptosis , Cobre , Especies Reactivas de Oxígeno , Rutenio , Cobre/química , Cobre/farmacología , Humanos , Especies Reactivas de Oxígeno/metabolismo , Animales , Rutenio/química , Rutenio/farmacología , Apoptosis/efectos de los fármacos , Ratones , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Ligandos , Ferroptosis/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.
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Cancer continues to be leading cause of morbidity and mortality despite decades of research and advancement in chemotherapy. Most tumors can be reduced via standard oncology treatments, such as chemotherapy, radiotherapy, and surgical resection, and they frequently recur. Significant progress has been made since targeted cancer therapy inception in creation of medications that exhibit improved tumor-selective action. Particularly in preclinical and clinical investigations, fusion proteins have shown strong activity and improved treatment outcomes for a number of human cancers. Synergistically combining many proteins into one complex allows the creation of synthetic fusion proteins with enhanced characteristics or new capabilities. Signal transduction pathways are important for onset, development, and spread of cancer. As result, signaling molecules are desirable targets for cancer therapies, and significant effort has been made into developing fusion proteins that would act as inhibitors of these pathways. A wide range of biotechnological and medicinal applications are made possible by fusion of protein domains that improves bioactivities or creates new functional combinations. Such proteins may function as immune effectors cell recruiters to tumors or as decoy receptors for various ligands. In this review article, we have outlined the standard methods for creating fusion proteins and covered the applications of fusion proteins in treatment of cancer. This article also highlights the role of fusion proteins in targeting the signaling pathways involved in cancer for effective treatment.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Biotecnología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase (MAPK) family, is involved in key cellular processes. However, overexpression and upregulation of ERK5 have been reported in various cancers, and ERK5 is associated with almost every biological characteristic of cancer cells. Accordingly, ERK5 has become a novel target for the development of anticancer drugs as inhibition of ERK5 shows suppressive effects of the deleterious properties of cancer cells. Herein, we report the synthesis and identification of a novel ERK5 inhibitor, MHJ-627, and verify its potent anticancer efficacy in a yeast model and the cervical cancer HeLa cell line. MHJ-627 successfully inhibited the kinase activity of ERK5 (IC50: 0.91 µM) and promoted the mRNA expression of tumor suppressors and anti-metastatic genes. Moreover, we observed significant cancer cell death, accompanied by a reduction in mRNA levels of the cell proliferation marker, proliferating cell nuclear antigen (PCNA), following ERK5 inhibition due to MHJ-627 treatment. We expect this finding to serve as a lead compound for further identification of inhibitors for ERK5-directed novel approaches for oncotherapy with increased specificity.
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Hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality but lacks effective treatments thus far. Although the emergence of immune checkpoint inhibitors in recent years has shed light on the treatment of HCC, a considerable number of patients are still unable to achieve durable and ideal clinical benefits. Therefore, refining the combination of immune checkpoint inhibitors (ICIs) to enhance the therapeutic effect has become a global research hotspot. Several histone deacetylase 2 inhibitors have shown advantages in ICIs in many solid cancers, except for HCC. Additionally, the latest evidence has shown that histone deacetylase 2 inhibition can regulate PD-L1 acetylation, thereby blocking the nuclear translocation of PD-L1 and consequently enhancing the efficacy of PD-1/PD-L1 inhibitors and improving anti-cancer immunity. Moreover, our team has recently discovered a novel HDAC2 inhibitor (HDAC2i), valetric acid (VA), that possesses great potential in HCC treatment as a monotherapy. Thus, a new combination strategy, combining HDAC2 inhibitors with ICIs, has emerged with significant development value. This perspective aims to ignite enthusiasm for exploring the application of ideal HDAC2 inhibitors with solid anti-tumor efficacy in combination with immunotherapy for HCC.
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In the wake of the development of metagenomic, metabolomic, and metatranscriptomic approaches, the intricate interactions between the host and various microbes are now being progressively understood. Numerous studies have demonstrated evident changes in gut microbiota during the process of a variety of diseases, such as diabetes, obesity, aging, and cancers. Notably, gut microbiota is viewed as a potential source of novel therapeutics. Currently, Next-generation probiotics (NGPs) are gaining popularity as therapeutic agents that alter the gut microbiota and affect cancer development. Akkermansia muciniphila (A. muciniphila), a representative commensal bacterium, has received substantial attention over the past decade as a promising NGP. The components and metabolites of A. muciniphila can directly or indirectly affect tumorigenesis, in particular through its effects on antitumor immunosurveillance, including the stimulation of pattern recognition receptors (PRRs), which also leads to better outcomes in a variety of situations, including the prevention and curation of cancers. In this article, we systematically summarize the role of A. muciniphila in tumorigenesis (involving gastrointestinal and non-gastrointestinal cancers) and in tumor therapy. In particular, we carefully discuss some critical scientific issues that need to be solved for the future using A. muciniphila as a representative beneficial bacterium in tumor treatment, which might provide bright clues and assistance for the application of drugs targeting A. muciniphila in clinical oncotherapy.
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Tumors are a major public health issue of concern to humans, seriously threatening the safety of people's lives and property. With the increasing demand for early and accurate diagnosis and efficient treatment of tumors, noninvasive optical imaging (including fluorescence imaging and photoacoustic imaging) and tumor synergistic therapies (phototherapy synergistic with chemotherapy, phototherapy synergistic with immunotherapy, etc.) have received increasing attention. In particular, light in the near-infrared second region (NIR-II) has triggered great research interest due to its penetration depth, minimal tissue autofluorescence, and reduced tissue absorption and scattering. Nanomaterials with many advantages, such as high brightness, great photostability, tunable photophysical properties, and excellent biosafety offer unlimited possibilities and are being investigated for NIR-II tumor imaging-guided synergistic oncotherapy. In recent years, many researchers have tried various approaches to investigate nanomaterials, including gold nanomaterials, two-dimensional materials, metal sulfide oxides, polymers, carbon nanomaterials, NIR-II dyes, and other nanomaterials for tumor diagnostic and therapeutic integrated nanoplatform construction. In this paper, the application of multifunctional nanomaterials in tumor NIR-II imaging and collaborative therapy in the past three years is briefly reviewed, and the current research status is summarized and prospected, with a view to contributing to future tumor therapy.
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Nanopartículas , Nanoestructuras , Neoplasias , Humanos , Fototerapia/métodos , Polímeros/uso terapéutico , Nanoestructuras/uso terapéutico , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Imagen Óptica , Nanomedicina Teranóstica/métodosRESUMEN
The Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome (KLHL 11-PNS) was first identified in 2019. This novel antibody, targeting the intracellular KLHL 11 antigen, can be detected in serum and cerebrospinal fluid using tissue-based and cell-based assays. It is thought to be a biomarker for a T-cell autoimmunity response. The most likely immunopathogenesis of KLHL 11-PNS appears to be linked to cytotoxic T-cell-mediated neuronal injury and loss. Patients have adult-male predilection, rhombencephalitis (brainstem and / or cerebellar involvement), and a robust oncological correlation with testicular germ cell tumors (predominately seminoma). Brain magnetic resonance imaging demonstrated T2 / fluid-attenuated inversion recovery hyperintensities and atrophy of the temporal lobe, cerebellum, and brainstem. Most patients responded poorly to immunotherapy and oncotherapy and thus had a poor long-term prognosis. We review the literature and provide an update of current knowledge regarding KLHL 11-PNS, including epidemiology, underlying mechanism, clinical presentations, paraclinical and oncological findings, diagnostic workup, and treatment approaches.
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Neoplasias de Células Germinales y Embrionarias , Síndromes Paraneoplásicos del Sistema Nervioso , Síndromes Paraneoplásicos , Neoplasias Testiculares , Adulto , Autoanticuerpos , Humanos , Masculino , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/terapiaRESUMEN
BACKGROUND: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Neoplasias del Recto , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Expresión Génica , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Células Neoplásicas Circulantes/patología , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Estudios RetrospectivosRESUMEN
In recent years, oncotherapy has received considerable attention concerning plant polyphenols. Increasing evidence suggests that because of the efficiency of polyphenols, they may have anti-tumour effects in various cancers. However, their regulatory structures remain elusive. Long non-coding RNAs (lncRNAs) have been identified in the regulation of various forms of tumorigenesis and tumour development. Long non-coding RNAs have recently emerged as regulatory eukaryotic transcripts and therapeutic targets with important and diverse functions in health and diseases. LncRNAs may be associated with the initiation, development, and progression of cancer. This review summarizes the research on the modulatory effects of IncRNAs and their roles in mediating cellular processes. The mechanisms of action of polyphenols underlying their therapeutic effects on cancers are also discussed. Based on our review, polyphenols might facilitate a significant epigenetic modification as part of their tissue- and/or cell-related biological effects. This finding may be attributed to their interaction with cellular signalling pathways involved in chronic diseases. Certain lncRNAs might be the target of specific polyphenols, and some critical signalling processes involved in the intervention of cancers might mediate the therapeutic roles of polyphenols.
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Neoplasias , ARN Largo no Codificante , Carcinogénesis , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Polifenoles/farmacología , Polifenoles/uso terapéutico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no TraducidoRESUMEN
BACKGROUND: Differentiated thyroid carcinoma (DTC) accounts for the vast majority of thyroid cancer (TC) cases. The rapidly increasing incidence of TC requires the urgent identification of new diagnostic and therapeutic targets. Solute carrier family 27 member 2 (SLC27A2/FATP2) plays an essential role in lipid biosynthesis and fatty acid transport. Recent studies have confirmed its involvement in a variety of diseases, including cancer. METHODS: In this study, the expression of SLC27A2 was analyzed in cancer and paracancerous tissue samples from 98 thyroid cancer patients, and we performed ROC analysis to confirm the diagnostic value. CCK8, Transwell, and other methods were used to study its effect on DTC, and the mechanism of SLC27A2 was investigated by RNA sequencing and Western blot. RESULTS: The expression of SLC27A2 was upregulated in both DTC tissues and cell lines and was correlated with clinical progression. In vitro studies further confirmed that SLC27A2 knockdown attenuated the proliferation and invasion of DTC cells. Through RNA sequence analysis and gene set enrichment analysis, we found that the MAPK pathway is the main downstream signaling pathway for the regulation by SLC27A2. SLC27A2 affects cell proliferation and differentiation by inducing changes in the proto-oncogene C-FOS. CONCLUSIONS: Our results show that SLC27A2 plays an important role in tumor proliferation and migration, providing a new putative target for the diagnosis and treatment of TC.
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Movimiento Celular/genética , Proliferación Celular/genética , Coenzima A Ligasas/genética , Neoplasias de la Tiroides , Coenzima A Ligasas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Regulación hacia Arriba/genéticaRESUMEN
Castration-resistant prostate cancer (CRPC) is the most common malignant tumor of the male urinary system. Nanodrug delivery systems (NDDS) have been widely applied in drug delivery for tumor therapy; however, nanotherapeutics encounter various biological barriers that prevent successful accumulation of drugs, specifically at diseased sites. Therefore, there is an urgent need to develop a CRPC-targeting nanocomposite with fine biocompatibility for penetrating various biological barriers, delivering sufficient drugs to the targeting site and improving therapeutic efficiency. In this work, CRPC cell membranes were firstly adapted as biomimetic vectors for the encapsulating PEG-PLGA polymer containing the chemotherapy drug docetaxel (DTX). The CRPC membrane-camouflaged nanoparticles can easily escape early recognition by the immune system, penetrate the extracellular barrier, and evade clearance by the circulatory system. In addition to the characteristics of traditional nanoparticles, the CRPC cell membrane contains an arsenal of highly specific homotypic moieties that can be used to recognize the same cancer cell types and increase the targeted drug delivery of DTX. In vivo fluorescence and radionuclide dual-model imaging were fulfilled by decorating the biomimetic nanosystem with near-infrared dye and isotope, which validated the homotypic targeting property offered by the CRPC cell membrane coating. Importantly, remarkably improved therapeutic efficacy was achieved in a mice model bearing CRPC tumors. This homologous cell membrane enabled an efficient drug delivery strategy and enlightened a new pathway for the clinical application of tumor chemotherapy drugs in the future.
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Antineoplásicos , Nanopartículas , Neoplasias de la Próstata Resistentes a la Castración , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomimética , Línea Celular Tumoral , Docetaxel/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Ratones , Nanopartículas/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
Precision oncotherapy can remove tumors without causing any apparent iatrogenic damage or irreversible side effects to normal tissues. Second near-infrared (NIR-II) nanotheranostics can simultaneously perform diagnostic and therapeutic modalities in a single nanoplatform, which exhibits prominent perspectives in tumor precision treatment. Among all NIR-II nanotheranostics, NIR-II organic nanotheranostics have shown an exceptional promise for translation in clinical tumor treatment than NIR-II inorganic nanotheranostics in virtue of their good biocompatibility, excellent reproducibility, desirable excretion, and high biosafety. In this review, recent progress of NIR-II organic nanotheranostics with the integration of tumor diagnosis and therapy is systematically summarized, focusing on the theranostic modes and performances. Furthermore, the current status quo, problems, and challenges are discussed, aiming to provide a certain guiding significance for the future development of NIR-II organic nanotheranostics for precision oncotherapy.
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Neoplasias , Nanomedicina Teranóstica , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Fototerapia , Reproducibilidad de los ResultadosRESUMEN
Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a 'real-time' picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy.
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Glioblastoma/terapia , Glioma/terapia , Anciano , Biomarcadores de Tumor/sangre , Encéfalo/metabolismo , Neoplasias Encefálicas/sangre , Epigénesis Genética/genética , Exosomas/metabolismo , Femenino , Humanos , Inmunoterapia , Biopsia Líquida/métodos , Masculino , Persona de Mediana Edad , Ácidos Nucleicos/sangre , PronósticoRESUMEN
Thrombotic microangiopathy (TMA) is an emerging complication of oncologic therapy. Cancer-related causes of renal endothelial cell damage include cytotoxic chemotherapies, radiation given for myeloablation, and direct involvement of renal vasculature by tumor cells. Another class of therapeutic agents that has been implicated in TMA is the vascular endothelial growth factor (VEGF) pathway inhibitors, including the anti-VEGF monoclonal antibody bevacizumab and the VEGF receptor tyrosine kinase inhibitor sunitinib. These TMAs have been termed type II cancer drug-induced TMA and are distinguished from those associated with some cytotoxic chemotherapies (ie, type I) in that they are not dose dependent and patients are more likely to demonstrate some recovery of kidney function. Determination of the cause of TMA in oncologic patients often presents a significant challenge because patients frequently receive multiple chemotherapeutic agents simultaneously and clinicopathologic features often demonstrate substantial overlap, regardless of cause. We present a case of TMA with predominantly chronic features in a 70-year-old patient being treated for adenoid cystic carcinoma of the breast with a single agent, a short interfering RNA targeted against Myc (DCR-MYC).
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Proteínas Proto-Oncogénicas c-myc/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/genética , Microangiopatías Trombóticas/inducido químicamente , Microangiopatías Trombóticas/genética , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Enfermedad Crónica , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Resultado Fatal , Femenino , Marcación de Gen/efectos adversos , Marcación de Gen/métodos , Humanos , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Microangiopatías Trombóticas/diagnósticoRESUMEN
Boron neutron capture therapy (BNCT) has received extensive attention as noninvasive cell-level oncotherapy for treating solid cancer tumors. However, boron-containing drugs such as l-boronophenylalanine (BPA) and sodium borocaptate have low boron content and/or poor tumor-targeting ability, limiting their application. In this study, we designed and synthesized a series of nontoxic, dual-target boron carriers (B139, B142, and B151) with the ability to accumulate specifically in tumor cells. We found that the B139 uptake into hypoxic tumor regions was high, with a 70-fold boron content compared to BPA. In addition, in vivo observation showed that B139 can be trapped in tumor cells for a prolonged period and maintains an effective therapeutic concentration, with a peak boron concentration of 50.7 µg/g and a high tumor: blood boron ratio of >3, achieving ideal BNCT conditions. Cytotoxicity evaluation in mice further proved that B139 is safe and reliable. Therefore, B139 has great potential for BNCT application as a dual-target, safe, and efficient boron carrier.
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Terapia por Captura de Neutrón de Boro , Neoplasias/radioterapia , Animales , Boranos/farmacología , Compuestos de Boro/química , Compuestos de Boro/metabolismo , Compuestos de Boro/farmacocinética , Compuestos de Boro/toxicidad , Hipoxia de la Célula , Línea Celular Tumoral , Humanos , Ratones , Nanopartículas/química , Nanopartículas/efectos de la radiación , Nanopartículas/uso terapéutico , Neoplasias/sangre , Neoplasias/enzimología , Neoplasias/metabolismo , Nitroimidazoles/química , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.
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Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Adulto , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Humanos , Biopsia Líquida/métodos , Persona de Mediana Edad , Proyectos PilotoRESUMEN
Metastatic spread, not primary tumors, is the leading cause of cancer death. Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is particularly relevant in cancer cells as it is involved in regulating carcinogenic mechanisms, growth and dissemination, and multidrug and radiation resistance. Upon interaction of metastatic cells with the vascular endothelium, a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium. GSH release from different organs, mainly the liver, and its interorgan transport through the blood circulation to metastatic foci, promote their growth. This review focuses on the relationship among GSH and different key mechanisms that facilitate metastatic cell survival and growth, i.e. adaptive responses to stress, cell death evasion and utilization of physiological neuroendocrine mechanisms. Different strategies that are aimed at sensitizing metastases to cancer therapy by depleting metastatic cell GSH are analyzed.
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Glutatión , Metástasis de la Neoplasia , Neoplasias , Animales , Glutatión/metabolismo , Glutatión/fisiología , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/fisiopatologíaRESUMEN
Phytochemicals as dietary constituents are being explored for their cancer preventive properties. Quercetin is a major constituent of various dietary products and recently its anti-cancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. Quercetin is known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, quercetin possesses great medicinal value, its applications as a therapeutic drug are limited. Problems like low oral bioavailability and poor aqueous solubility make quercetin an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of quercetin is also a major barrier for its clinical translation. Hence, to overcome these disadvantages quercetin-based nanoformulations are being considered in recent times. Nanoformulations of quercetin have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site. Herein we have tried to summarize various methods utilized for nanofabrication of quercetin formulations and for stable and sustained delivery of quercetin. We have also highlighted the various desirable measures for its use as a promising onco-therapeutic agent.