RESUMEN
Improving the efficacy of anticancer drugs is especially challenging. Estrogen is a sex hormone that not only promotes the development of female secondary sexual characteristics, but also supports many important physiological functions. Interestingly, estrogen has shown to be vital for the activity of some anticancer drugs, such as adriamycin, cisplatin, olaparib, trastuzumab, bevacizumab, tamoxifen, cyclophosphamide, methotrexate, and paclitaxel. Although there are many reasons for the differences in therapeutic effects among cancer patients, estrogen status is undoubtedly a very important factor. In view of the importance of the crosstalk between estrogen signaling and drug therapy for cancer, this review summarizes the effects of estrogen on the targets, metabolism and resistance of anticancer drugs and describes the related pathways and underlying mechanisms. Here, an analysis of the close relationship between estrogen and cancer drug therapy was conducted to clarify the effects of estrogen on the therapeutic efficacy of anticancer drugs to facilitate the future development of specific drug treatment strategies to achieve optimal outcomes.
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cisplatino/farmacología , Estrógenos/uso terapéutico , Femenino , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Tamoxifeno/uso terapéuticoRESUMEN
Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Animales , Resistencia a Antineoplásicos , HumanosRESUMEN
Colorectal cancer (CRC) is one of the most common causes of cancer death worldwide. While standard chemotherapy and new targeted therapy have been improved recently, problems such as multidrug resistance (MDR) and severe side effects remain unresolved. RNAs are essential to all biological processes including cell proliferation and differentiation, cell cycle, apoptosis, activation of tumor suppressor genes, suppression of oncogenes. Therefore, there are various potential approaches to address genetic disease like CRC at the RNA level. In contrast to conventional treatments, RNA-based therapeutics such as RNA interference, antisense oligonucleotides, RNA aptamer, ribozymes, have the advantages of high specificity, high potency and low toxicity. It has gained more and more attention due to the flexibility in modulating a wide range of targets. Here, we highlight recent advances and clinical studies involving RNA-based therapeutics and CRC. We also discuss their advantages and limitations that remain to be overcome for the treatment of human CRC.
Asunto(s)
Neoplasias Colorrectales/terapia , ARN/uso terapéutico , Animales , Humanos , Resultado del TratamientoRESUMEN
Twenty-five years ago, the cytotoxic drug irinotecan (IRT) was first approved in Japan for the treatment of cancer. For more than two decades, the IRT prodrug has largely contributed to the treatment of solid tumors worldwide. Nowadays, this camptothecin derivative targeting topoisomerase 1 remains largely used in combination regimen, like FOLFIRI and FOLFIRINOX, to treat metastatic or advanced solid tumors, such as colon, gastric and pancreatic cancers and others. This review highlights recent discoveries in the field of IRT and its derivatives, including analogues of the active metabolite SN38 (such as FL118), the recently approved liposomal form Nal-IRI and SN38-based immuno-conjugates currently in development (such as sacituzumab govitecan). New information about the IRT mechanism of action are presented, including the discovery of a new protein target, the single-stranded DNA-binding protein FUBP1. Significant progress has been made also to better understand and manage the main limiting toxicities of IRT, chiefly neutropenia and diarrhea. The role of drug-induced inflammation and dysbiosis is underlined and strategies to limit the intestinal toxicity of IRT are discussed (use of ß-glucuronidase inhibitors, plant extracts, probiotics). The detailed knowledge of the metabolism of IRT has enabled the identification of potential biomarkers to guide patient selection and to limit drug-induced toxicities, but no robust IRT-specific therapeutic biomarker has been approved yet. IRT is a versatile chemotherapeutic agent which combines well with a variety of anticancer drugs. It offers a large range of drug combinations with cytotoxic agents, targeted products and immuno-active biotherapeutics, to treat a variety of advanced solid carcinoma, sarcoma and cancers with progressive central nervous system diseases. A quarter of century after its first launch, IRT remains an essential anticancer drug, largely prescribed, useful to many patients and scientifically inspiring.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Irinotecán/farmacología , Irinotecán/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/metabolismoRESUMEN
The dynamic and delicate interactions amongst intestinal microbiota, metabolome and metabolism dictates human health and disease. In recent years, our understanding of gut microbial regulation of intestinal immunometabolic and redox homeostasis have evolved mainly out of in vivo studies associated with high-fat feeding induced metabolic diseases. Techniques utilizing fecal transplantation and germ-free mice have been instrumental in reproducibly demonstrating how the gut microbiota affects disease pathogenesis. However, the pillars of modern drug discovery i.e. evidence-based pharmacological studies critically lack focus on intestinal microflora. This is primarily due to targeted in vitro molecular-approaches at cellular-level that largely overlook the etiology of disease pathogenesis from the physiological perspective. Thus, this review aims to provide a comprehensive understanding of the key notions of intestinal microbiota and dysbiosis, and highlight the microbiota-phytochemical bidirectional interactions that affects bioavailability and bioactivity of parent phytochemicals and their metabolites. Potentially by focusing on the three major aspects of gut microbiota i.e. microbial abundance, diversity, and functions, I will discuss phytochemical-microbiota reciprocal interactions, biotransformation of phytochemicals and plant-derived drugs, and pre-clinical and clinical efficacies of herbal medicine on dysbiosis. Additionally, in relation to phytochemical pharmacology, I will briefly discuss the role of dietary-patterns associated with changes in microbial profiles and review pharmacological study models considering possible microbial effects. This review therefore, emphasize on the timely and critically needed evidence-based phytochemical studies focusing on gut microbiota and will provide newer insights for future pre-clinical and clinical phytopharmacological interventions.
Asunto(s)
Microbioma Gastrointestinal/efectos de los fármacos , Fitoquímicos/farmacología , Fitoterapia , Animales , Biotransformación , Dieta , Humanos , Fitoquímicos/farmacocinéticaRESUMEN
The ability of an antineoplastic drug to exert its cytostatic effect depends largely on the balance between its uptake into and extrusion from the cancer cells. ATP driven efflux transporter proteins drive the export of antineoplastic drugs and play a pivotal role in the development of chemoresistance. As regards uptake transporters, comparably less is known on their impact in drug action. In the current study, we characterized the interactions of two uptake transporter proteins, expressed mainly in the liver; the organic anion transporter 2 (OAT2, encoded by the SLC22A7 gene) and the sodium taurocholate cotransporting polypeptide (NTCP, encoded by the SLC10A1 gene), stably transfected in human embryonic kidney cells, with some antineoplastic agents that are routinely being used in cancer chemotherapy. Whereas NTCP did not show any strong interactions with the cytostatics tested, we observed a very strong inhibition of OAT2 mediated [(3)H] cGMP uptake in the presence of bendamustine, irinotecan and paclitaxel. The Ki values of OAT2 for bendamustine, irinotecan and paclitaxel were determined to be 43.3±4.33µM, 26.4±2.34µM and 10.4±0.45µM, respectively. Incubation of bendamustine with OAT2 expressing cells increased the caspase-3 activity, and this increase was inhibited by simultaneous incubation with bendamustine and probenecid, a well-known inhibitor of OATs, suggesting that bendamustine is a substrate of OAT2. A higher accumulation of irinotecan was observed in OAT2 expressing cells compared to control pcDNA cells by HPLC analysis of cell lysates. The accumulation was diminished in the presence of cGMP, the substrate we used to functionally characterize OAT2, suggesting specificity of this uptake and the fact that OAT2 mediates uptake of irinotecan.
Asunto(s)
Antineoplásicos/farmacología , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Simportadores/metabolismo , Apoptosis/efectos de los fármacos , Clorhidrato de Bendamustina , Transporte Biológico , Camptotecina/análogos & derivados , Camptotecina/farmacología , GMP Cíclico/metabolismo , Estrona/análogos & derivados , Estrona/metabolismo , Células HEK293 , Humanos , Irinotecán , Compuestos de Mostaza Nitrogenada/farmacología , Paclitaxel/farmacologíaRESUMEN
Glioma is a kind of lethal malignant tumor, and lacks efficient therapies. Combination therapy has been claimed to be a promising approach to combat cancer, due to its increased anti-cancer effects and reduced side effects. This study aimed to investigate the anti-cancer effect and mechanism of combining imatinib with irinotecan or its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). First, we found that this drug combination exerted synergistic antitumor effects against glioma in vitro and in vivo. In addition, flow cytometry results proved that the SN-38-induced apoptosis was further enhanced by imatinib, and similar results were observed by determining the protein expression levels of apoptosis biomarkers. Interestingly, p53 expression was elevated by the SN-38 mono-treatment, and was not further increased after the co-treatment; besides, knockdown of p53 could only reduce the expression of cleaved-PARP partially, and weaken the enhanced proliferation inhibition induced by SN-38 plus imatinib, indicating that there might be other factors involved in the synergistic effects besides p53. Meanwhile, the markedly elevated p21 expression was observed only in the combination group, instead of the mono-treated groups. According to the results of p21 knockdown, we found that p21 was also required for the synergistic inhibitory effects. Moreover, we explored and ruled out the possibility of imatinib enhancing the sensitivity of irinotecan by inhibiting drug efflux pumps. Thus, our findings collectively suggest that combining irinotecan with imatinib could be a promising new strategy to fight against glioma.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glioma/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Irinotecán/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Glioma/patología , Humanos , Mesilato de Imatinib/farmacología , Irinotecán/farmacología , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE, and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , ADN/genética , Antineoplásicos Fitogénicos/metabolismo , Camptotecina/metabolismo , Línea Celular Tumoral , ADN/química , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Irinotecán , Unión Proteica , Proteínas de Unión al ARNRESUMEN
Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Líquido Extracelular/metabolismo , Inmunoglobulina G/administración & dosificación , N-Acetilgalactosaminiltransferasas/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Neuroblastoma/metabolismo , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales de Origen Murino , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/química , Camptotecina/farmacocinética , Línea Celular Tumoral , Preescolar , Liberación de Fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoglobulina G/química , Irinotecán , Masculino , Ratones Desnudos , N-Acetilgalactosaminiltransferasas/genética , N-Acetilgalactosaminiltransferasas/inmunología , N-Acetilgalactosaminiltransferasas/metabolismo , Nanopartículas/química , Neuroblastoma/tratamiento farmacológico , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Embolic microspheres or beads used in transarterial chemoembolization are an established treatment method for hepatocellular carcinoma patients. The occlusion of the tumor-feeding vessels by intra-arterial injection of the beads results in tumor necrosis and shrinkage. In this short review, we describe the utility of using these beads as devices for local drug delivery. We review the latest advances in the development of non-biodegradable and biodegradable drug-eluting beads for transarterial chemoembolization. Their capability to load different drugs, such as chemotherapeutics and anti-angiogenic compounds with different physicochemical properties, like charge and hydrophilicity/hydrophobicity, are discussed. We specifically address controlled and sustained drug release from the microspheres, and the resulting in vivo pharmacokinetics in the plasma vs. drug distribution in the targeted tissue.
Asunto(s)
Quimioembolización Terapéutica , Sistemas de Liberación de Medicamentos , Microesferas , Animales , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/uso terapéutico , HumanosRESUMEN
It has been a major challenge for drug penetration in solid tumor tissues because of the complicated tumor microenvironment. We have previously constructed a protein of bispecific targets and high permeability named anti-EGFR-iRGD and investigated its inhibiting cell proliferation of gastric cancer. Paclitaxel (PTX) is widely used for treating various kinds of cancer. In this paper, we investigated the effects of anti-EGFR-iRGD in combination with chemotherapeutic drugs including PTX in epidermal growth factor receptor highly expressing gastric cancer. We demonstrated the therapeutic efficacy of PTX combined with anti-EGFR-iRGD on monolayer cells (2D), multicellular spheroids (3D) and tumor-bearing mice for the first time and investigated the mechanism of this synergy effect. Our results provide impetus for further studies to use anti-EGFR-iRGD with standard cytotoxic treatment regimens for enhancing therapy of gastric cancer patients.