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1.
Adv Exp Med Biol ; 1295: 77-95, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543456

RESUMEN

Nanomedicine has been a hot topic in the field of tumor therapy in the past few decades. Because of the enhanced permeability and retention effect (EPR effect), nanomedicine can passively yet selectively accumulate at tumor tissues. As a result, it can improve drug concentration in tumor tissues and reduce drug distribution in normal tissues, thereby contributing to enhanced antitumor effect and reduced adverse effects. However, the therapeutic efficacy of anticancer nanomedicine is not satisfactory in clinical settings. Therefore, how to improve the clinical therapeutic effect of nanomedicine has become an urgent problem. The grand challenges of nanomedicine lie in how to overcome various pathophysiological barriers and simultaneously kill cancer cells effectively in hypoxic tumor microenvironment (TME). To this end, the development of novel stimuli-responsive nanomedicine has become a new research hotspot. While a great deal of progress has been made in this direction and preclinical results report many different kinds of promising multifunctional smart nanomedicine, the design of these intelligent nanomedicines is often too complicated, the requirements for the preparation processes are strict, the cost is high, and the clinical translation is difficult. Thus, it is more practical to find solutions to promote the therapeutic efficacy of commercialized nanomedicines, for example, Doxil®, Oncaspar®, DaunoXome®, Abraxane®, to name a few. Increasing attention has been paid to the combination of modern advanced medical technology and nanomedicine for the treatment of various malignancies. Recently, we found that hyperbaric oxygen (HBO) therapy could enhance Doxil® antitumor efficacy. Inspired by this study, we further carried out researches on the combination of HBO therapy with other nanomedicines for various cancer therapies, and revealed that HBO therapy could significantly boost antitumor efficacy of nanomedicine-mediated photodynamic therapy and photothermal therapy in different kinds of tumors, including hepatocellular carcinoma, breast cancer, and gliomas. Our results implicate that HBO therapy might be a universal strategy to boost therapeutic efficacy of nanomedicine against hypoxic solid malignancies.


Asunto(s)
Antineoplásicos , Oxigenación Hiperbárica , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Nanomedicina , Neoplasias/tratamiento farmacológico , Microambiente Tumoral
2.
Adv Exp Med Biol ; 1295: 271-299, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33543464

RESUMEN

Multiple studies about tumor biology have revealed the determinant role of the tumor microenvironment in cancer progression, resulting from the dynamic interactions between tumor cells and surrounding stromal cells within the extracellular matrix. This malignant microenvironment highly impacts the efficacy of anticancer nanoparticles by displaying drug resistance mechanisms, as well as intrinsic physical and biochemical barriers, which hamper their intratumoral accumulation and biological activity.Currently, two-dimensional cell cultures are used as the initial screening method in vitro for testing cytotoxic nanocarriers. However, this fails to mimic the tumor heterogeneity, as well as the three-dimensional tumor architecture and pathophysiological barriers, leading to an inaccurate pharmacological evaluation.Biomimetic 3D in vitro tumor models, on the other hand, are emerging as promising tools for more accurately assessing nanoparticle activity, owing to their ability to recapitulate certain features of the tumor microenvironment and thus provide mechanistic insights into nanocarrier intratumoral penetration and diffusion rates.Notwithstanding, in vivo validation of nanomedicines remains irreplaceable at the preclinical stage, and a vast variety of more advanced in vivo tumor models is currently available. Such complex animal models (e.g., genetically engineered mice and patient-derived xenografts) are capable of better predicting nanocarrier clinical efficiency, as they closely resemble the heterogeneity of the human tumor microenvironment.Herein, the development of physiologically more relevant in vitro and in vivo tumor models for the preclinical evaluation of anticancer nanoparticles will be discussed, as well as the current limitations and future challenges in clinical translation.


Asunto(s)
Antineoplásicos , Nanopartículas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nanomedicina , Esferoides Celulares , Microambiente Tumoral
3.
Cells ; 10(2)2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540625

RESUMEN

Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-2) pandemic, arace to develop a vaccine has been initiated, considering the massive and rather significant economic and healthcare hits that this virus has caused. The pathophysiology occurring following COVID-19(coronavirus disease-2019) infection has givenhints regarding the supportive and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications. Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients are at higher risk of viral infection and more likely to develop serious complications due to their immunocompromised state, the fact that they are already administering multiple medications, as well as combined comorbidity compared to the general population. It may seem impossible to find a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19 infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive COVID-19 therapy and cancer therapy, and finally, its anticancer effects.


Asunto(s)
Antineoplásicos , Antivirales , Benzoquinonas , Reposicionamiento de Medicamentos , Neoplasias , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , Benzoquinonas/farmacología , Benzoquinonas/uso terapéutico , /tratamiento farmacológico , Línea Celular Tumoral , Humanos , Ratones , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Ratas
4.
Nat Commun ; 12(1): 898, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563973

RESUMEN

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.


Asunto(s)
Tolerancia a Radiación , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Int J Nanomedicine ; 16: 579-589, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531802

RESUMEN

Purpose: Breast cancer is one of the most lethal types of cancer in women. Curcumin showed therapeutic potential against breast cancer, but applying that by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Moreover, poor water solubility of curcumin causes accumulation of a high concentration of curcumin and so decrease its permeability to the cell. Many strategies are employed to reduce curcumin metabolism such as adjuvants and designing novel delivery systems. Therefore, in this study sodium alginate and chitosan were used to synthesize the hydrogels that are known as biocompatible, hydrophilic and low toxic drug delivery systems. Also, folic acid was used to link to chitosan in order to actively targetfolate receptors on the cells. Methods: Chitosan-ß-cyclodextrin-TPP-Folic acid/alginate nanoparticles were synthesized and then curcumin was loaded on them. Interaction between the constituents of the particles was characterized by FTIR spectroscopy. Morphological structures of samples were studied by FE-SEM. Release profile of curcumin was determined by dialysis membrane. The cytotoxic test was done on the Kerman male breast cancer (KMBC-10) cell line by using MTT assay. The viability of cells was detected by fluorescent staining. Gene expression was investigated by real-time PCR. Results: The encapsulation of curcumin into nano-particles showed an almost spherical shape and an average particle size of 155 nm. In vitro cytotoxicity investigation was indicated as dose-respond reaction against cancer breast cells after 24 h incubation. On the other hand, in vitro cell uptake study revealed active targeting of CUR-NPs into spheroids. Besides, CXCR 4 expression was detected about 30-fold less than curcumin alone. The CUR-NPs inhibited proliferation and increased apoptosis in spheroid human breast cancer cells. Conclusion: Our results showed the potential of NPs as an effective candidate for curcumin delivery to the target tumor spheroids that confirmed the creatable role of folate receptors.


Asunto(s)
Alginatos/química , Quitosano/química , Curcumina/farmacología , Nanosferas/química , Esferoides Celulares/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Fluorescencia , Ácido Fólico/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Nanosferas/ultraestructura , Tamaño de la Partícula , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Esferoides Celulares/efectos de los fármacos
6.
Med Clin North Am ; 105(2): 227-245, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33589099

RESUMEN

Immune checkpoint inhibitors activate the immune system to combat cancer. In doing so, however, they can cause immune-related adverse events (irAEs), including rheumatic syndromes, such as inflammatory arthritis, polymyalgia rheumatica, and myositis. This article reviews rheumatic irAEs that may be encountered in the general medicine practice and provides guidance to support prompt recognition, referral, and treatment of these patients.


Asunto(s)
Neoplasias/tratamiento farmacológico , Enfermedades Reumáticas , Antineoplásicos/inmunología , Antineoplásicos/farmacología , Humanos , /farmacología , Enfermedades Reumáticas/inducido químicamente , Enfermedades Reumáticas/inmunología , Enfermedades Reumáticas/terapia
7.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589584

RESUMEN

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Mieloma Múltiple/tratamiento farmacológico , Coactivador 3 de Receptor Nuclear/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Resistencia a Antineoplásicos/genética , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Coactivador 3 de Receptor Nuclear/antagonistas & inhibidores , Coactivador 3 de Receptor Nuclear/metabolismo , Inhibidores de Proteasoma/farmacología , Recurrencia , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Nat Commun ; 12(1): 117, 2021 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-33402692

RESUMEN

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.


Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Regulación Neoplásica de la Expresión Génica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Recurrencia Local de Neoplasia/genética , Receptores de Somatostatina/genética , Proteínas de la Matriz Viral/genética , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Infecciones por Virus de Epstein-Barr/mortalidad , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Herpesvirus Humano 4/patogenicidad , Interacciones Huésped-Patógeno/genética , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , FN-kappa B/genética , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/virología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/virología , Octreótido/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptores de Somatostatina/antagonistas & inhibidores , Receptores de Somatostatina/metabolismo , Transducción de Señal , Análisis de Supervivencia , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas de la Matriz Viral/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
BMC Bioinformatics ; 22(1): 13, 2021 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-33407085

RESUMEN

BACKGROUND: Predicting the drug response of the cancer diseases through the cellular perturbation signatures under the action of specific compounds is very important in personalized medicine. In the process of testing drug responses to the cancer, traditional experimental methods have been greatly hampered by the cost and sample size. At present, the public availability of large amounts of gene expression data makes it a challenging task to use machine learning methods to predict the drug sensitivity. RESULTS: In this study, we introduced the WRFEN-XGBoost cell viability prediction algorithm based on LINCS-L1000 cell signatures. We integrated the LINCS-L1000, CTRP and Achilles datasets and adopted a weighted fusion algorithm based on random forest and elastic net for key gene selection. Then the FEBPSO algorithm was introduced into XGBoost learning algorithm to predict the cell viability induced by the drugs. The proposed method was compared with some new methods, and it was found that our model achieved good results with 0.83 Pearson correlation. At the same time, we completed the drug sensitivity validation on the NCI60 and CCLE datasets, which further demonstrated the effectiveness of our method. CONCLUSIONS: The results showed that our method was conducive to the elucidation of disease mechanisms and the exploration of new therapies, which greatly promoted the progress of clinical medicine.


Asunto(s)
Algoritmos , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Biología Computacional/métodos , Línea Celular Tumoral , Bases de Datos Factuales , Humanos
10.
Theranostics ; 11(2): 731-753, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33391502

RESUMEN

The coronavirus disease 2019 (COVID-19) is a viral disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the respiratory system of infected individuals. COVID-19 spreads between humans through respiratory droplets produced when an infected person coughs or sneezes. The COVID-19 outbreak originated in Wuhan, China at the end of 2019. As of 29 Sept 2020, over 235 countries, areas or territories across the globe reported a total of 33,441,919 confirmed cases, and 1,003,497 confirmed deaths due to COVID-19. Individuals of all ages are at risk for infection, but in most cases disease severity is associated with age and pre-existing diseases that compromise immunity, like cancer. Numerous reports suggest that people with cancer can be at higher risk of severe illness and related deaths from COVID-19. Therefore, managing cancer care under this pandemic is challenging and requires a collaborative multidisciplinary approach for optimal care of cancer patients in hospital settings. In this comprehensive review, we discuss the impact of the COVID-19 pandemic on cancer patients, their care, and treatment. Further, this review covers the SARS-CoV-2 pandemic, genome characterization, COVID-19 pathophysiology, and associated signaling pathways in cancer, and the choice of anticancer agents as repurposed drugs for treating COVID-19.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , /genética , Antineoplásicos/farmacología , /inmunología , Comorbilidad , Reposicionamiento de Medicamentos , Genoma Viral/genética , Humanos , Neoplasias/epidemiología , Pandemias/prevención & control , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología
11.
BMC Bioinformatics ; 22(1): 15, 2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413081

RESUMEN

BACKGROUND: One of the current directions of precision medicine is the use of computational methods to aid in the diagnosis, prognosis, and treatment of disease based on data driven approaches. For instance, in oncology, there has been a particular focus on development of algorithms and biomarkers that can be used for pre-clinical and clinical applications. In particular large-scale omics-based models to predict drug sensitivity in in vitro cancer cell line panels have been used to explore the utility and aid in the development of these models as clinical tools. Additionally, a number of web-based interfaces have been constructed for researchers to explore the potential of drug perturbed gene expression as biomarkers including the NCI Transcriptional Pharmacodynamic Workbench. In this paper we explore the influence of drug perturbed gene dynamics of the NCI Transcriptional Pharmacodynamics Workbench in computational models to predict in vitro drug sensitivity for 15 drugs on the NCI60 cell line panel. RESULTS: This work presents three main findings. First, our models show that gene expression profiles that capture changes in gene expression after 24 h of exposure to a high concentration of drug generates the most accurate predictive models compared to the expression profiles under different dosing conditions. Second, signatures of 100 genes are developed for different gene expression profiles; furthermore, when the gene signatures are applied across gene expression profiles model performance is substantially decreased when gene signatures developed using changes in gene expression are applied to non-drugged gene expression. Lastly, we show that the gene interaction networks developed on these signatures show different network topologies and can be used to inform selection of cancer relevant genes. CONCLUSION: Our models suggest that perturbed gene signatures are predictive of drug response, but cannot be applied to predict drug response using unperturbed gene expression. Furthermore, additional drug perturbed gene expression measurements in in vitro cell lines could generate more predictive models; but, more importantly be used in conjunction with computational methods to discover important drug disease relationships.


Asunto(s)
Antineoplásicos , Biología Computacional/métodos , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Redes Reguladoras de Genes/efectos de los fármacos , Humanos
12.
Ecotoxicol Environ Saf ; 208: 111752, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396077

RESUMEN

Arsenic is a toxic heavy metal vastly dispersed all over the earth crust. It manifests several major adverse health issues to millions of arsenic exposed populations. Arsenic is associated with different types of cancer, cardiovascular disorders, diabetes, hypertension and many other diseases. On the contrary, arsenic (arsenic trioxide, As2O3) is used as a chemotherapeutic agent in the treatment of acute promyelocytic leukemia. Balance between arsenic induced cellular proliferations and apoptosis finally decide the outcome of its transformation rate. Arsenic propagates signals via cellular and nuclear pathways depending upon the chemical nature, and metabolic-fates of the arsenical compounds. Arsenic toxicity is propagated via ROS induced stress to DNA-repair mechanism and mitochondrial stability in the cell. ROS induced alteration in p53 regulation and some mitogen/ oncogenic functions determine the transformation outcome influencing cyclin-cdk complexes. Growth factor regulator proteins such as c-Jun, c-fos and c-myc are influenced by chronic arsenic exposure. In this review we have delineated arsenic induced ROS regulations of epidermal growth factor receptor (EGFR), NF-ĸß, MAP kinase, matrix-metalloproteinases (MMPs). The role of these signaling molecules has been discussed in relation to cellular apoptosis, cellular proliferation and neoplastic transformation. The arsenic stimulated pathways which help in proliferation and neoplastic transformation ultimately resulted in cancer manifestation whereas apoptotic pathways inhibited carcinogenesis. Therapeutic strategies against arsenic should be designed taking into account all these factors.


Asunto(s)
Arsénico/fisiología , Proliferación Celular/fisiología , Plásticos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsénico/metabolismo , Trióxido de Arsénico/metabolismo , Trióxido de Arsénico/farmacología , Arsenicales/metabolismo , Proliferación Celular/efectos de los fármacos , Humanos , Mitocondrias/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias , Óxidos/toxicidad , Transducción de Señal/efectos de los fármacos
13.
J Cancer Res Clin Oncol ; 147(1): 3-22, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33389079

RESUMEN

PURPOSE: This paper reviews marine compounds that target the mitogen-activated protein kinase (MAPK) signaling pathway and their main sources, chemical structures, major targeted cancers and possible mechanisms to provide comprehensive and basic information for the development of marine compound-based antitumor drugs in clinical cancer therapy research. METHODS: This paper searched the PubMed database using the keywords "cancer", "marine*" and "MAPK signaling pathway"; this search was supplemented by the literature-tracing method. The marine compounds screened for review in this paper are pure compounds with a chemical structure and have antitumor effects on more than one tumor cell line by targeting the MAPK signaling pathway. The PubChem database was used to search for the PubMed CID and draw the chemical structures of the marine compounds. RESULTS: A total of 128 studies were searched, and 32 marine compounds with unique structures from extensive sources were collected for this review. These compounds are cytotoxic to cancer cell lines, although their targets are still unclear. This paper describes their anticancer effect mechanisms and the protein expression changes in the MAPK pathway induced by these marine compound treatments. This review is the first to highlight MAPK signaling pathway-targeted marine compounds and their use in cancer therapy. CONCLUSION: The MAPK signaling pathway is a promising potential target for cancer therapy. Searching for marine compounds that exert anticancer effects by targeting the MAPK signaling pathway and developing them into new marine anticancer drugs will be beneficial for cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Organismos Acuáticos/química , Descubrimiento de Drogas , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Animales , Humanos , Neoplasias/enzimología , Neoplasias/patología
14.
Anticancer Res ; 41(1): 27-42, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419797

RESUMEN

BACKGROUND/AIM: We have tested whether the anticancer peptide, PNC-27, that kills cancer cells but not normal cells by binding to cancer cell membrane HDM-2 forming pores, kills CD44+ colon cancer stem cells. MATERIALS AND METHODS: Flow cytometry determined the CD44 and HDM-2 expression on six-colon cancer cell lines and one normal cell line (CCD-18Co). MTT, LDH release, annexin V binding and caspase 3 assays were used to assess PNC-27-induced cell death. Bioluminescence imaging measured PNC-27 effects on in vivo tumor growth. RESULTS: High percentages of cells in all six tumor lines expressed CD44. PNC-27 co-localized with membrane HDM-2 only in the cancer cells and caused total cell death (tumor cell necrosis, high LDH release, negative annexin V and caspase 3). In vivo, PNC-27 caused necrosis of tumor nodules but not of normal tissue. CONCLUSION: PNC-27 selectively kills colon cancer stem cells by binding of this peptide to membrane H/MDM-2.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor , Neoplasias del Colon/etiología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Animales , Antineoplásicos/uso terapéutico , Biomarcadores , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Humanos , Receptores de Hialuranos/metabolismo , Ratones , Terapia Molecular Dirigida , Necrosis/patología , Unión Proteica , Proteína p53 Supresora de Tumor/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Anticancer Res ; 41(1): 91-99, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419802

RESUMEN

BACKGROUND/AIM: Small-cell lung cancer (SCLC) is aggressive and confers poor prognosis. Although SCLC shows more response to chemotherapy than other types of lung cancer, it is difficult to cure because of its frequent recurrence. New drugs and molecular targets need to be identified. MATERIALS AND METHODS: We investigated the effect of nelfinavir, an HIV protease inhibitor, on SCLC cells and in preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. RESULTS: Nelfinavir inhibited SCLC cell proliferation and induced cell death in vitro, which was caused by induction of the unfolded protein response (UPR), inhibition of mammalian/mechanistic target of rapamycin (mTOR) activation, and reduction in the expression of SCLC-related molecules such as achaete-scute homolog 1 (ASCL1). In vivo, nelfinavir inhibited the growth of SCLC PDX tumors, which correlated with the induction of UPR and reduced expression of ASCL1. CONCLUSION: Nelfinavir is highly effective in SCLC in vitro and in vivo, suggesting possible incorporation of nelfinavir into clinical trials for patients with SCLC.


Asunto(s)
Antineoplásicos/farmacología , Reposicionamiento de Medicamentos , Nelfinavir/farmacología , Animales , Antineoplásicos/uso terapéutico , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Nelfinavir/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/patología , Serina-Treonina Quinasas TOR/metabolismo , Respuesta de Proteína Desplegada/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Anticancer Res ; 41(1): 123-130, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419805

RESUMEN

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is a serious disease and the leading cause of death globally. Overexpression of protein kinase B/nuclear factor-kappa B (NF-κB) signaling transduction of NSCLC cells was recognized as a potential therapeutic target. Lenvatinib is a multiple kinase inhibitor against vascular endothelial growth factor receptor family. However, whether lenvatinib may affect AKT/NF-κB in NSCLC remains unknown. MATERIALS AND METHODS: MTT assay, NF-κB reporter gene assay, flow cytometry, tranwell migration/invasion analysis and western blotting were used to identify the alteration of cell viability, NF-κB activation, apoptosis effect, migration/invasion potential and AKT/NF-κB related protein expression, respectively, in CL-1-5-F4 cells after lenvatinib treatment. RESULTS: The cell viability and NF-κB activity were suppressed by lenvatinib. Extrinsic and intrinsic apoptosis were activated by lenvatinib. Additionally, the metastatic potential of CL-1-5-F4 cells was also suppressed by lenvatinib. CONCLUSION: Altogether, lenvatinib induced extrinsic/intrinsic apoptosis and suppressed migration/invasion ability of NSCLC cells that was associated with AKT/NF-κB signaling inactivation.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Inhibidores de Proteínas Quinasas/farmacología
17.
Anticancer Res ; 41(1): 137-149, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419807

RESUMEN

BACKGROUND/AIM: Conventional viability tests, help to screen the cellular effects of candidate molecules, but the endpoint of these measurements lacks sufficient information regarding the molecular aspects. A non-invasive, easy-to-setup live-cell microscopic method served to in-depth analysis of mechanisms of potential anticancer drugs. MATERIALS AND METHODS: The proposed method combining the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test with time-lapse scanning microscopy (TLS), provided additional data related to the cell-cycle and the dynamic properties of cell morphology. Apoptotic and necrotic events became detectable with these methods. RESULTS: Quantification of the results was assisted by image analysis of the acquired image sequences. After demonstrating the potential of the TLS method, a series of experiments compared the in vitro effect of a known and a newly synthesized nucleoside analogue. CONCLUSION: The proposed approach provided a more in-depth insight into the cellular processes that can be affected by known chemotherapeutic agents including nucleoside analogues rather than applying repeated individual treatments.


Asunto(s)
Antineoplásicos/farmacología , Nucleósidos/farmacología , Sales de Tetrazolio , Tiazoles , Imagen de Lapso de Tiempo , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Microscopía , Nucleósidos/análogos & derivados , Imagen de Lapso de Tiempo/métodos
18.
Anticancer Res ; 41(1): 211-218, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419815

RESUMEN

BACKGROUND/AIM: Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. Recently, acidity has been implicated in inflammatory responses, which are mediated through active lipid metabolites in various human tissues. In the present study, we investigated whether acidity can affect lipid-mediated signaling, and found that phospholipase A2 (PLA2) activity increased at acidic pH in SNU601 and AGS gastric carcinoma cell lines. MATERIALS AND METHODS: To identify the PLA2 isoform that is responsible for the acidity-induced activity, we assessed mRNA levels of cPLA2 isotypes through real-time qPCR, and protein levels through immunoblot assay in cells cultured in acidic medium. RESULTS: It was found that acidic pH conditions markedly elevated the PLA2γ expression. A gene interference study using specific siRNA of cPLA2γ suggested that expression of cPLA2γ in acidic culture conditions may be associated with protection of cancer cells in acidic environment, as shown by cell viability and clonogenic assays. In addition, expression of cPLA2γ appeared to confer cell resistance to anticancer drugs under acidic pH conditions. CONCLUSION: Acidity-induced cPLA2γ expression may exert protective effects by imparting resistance to the gastric cancer cells under acidic environment.


Asunto(s)
Resistencia a Antineoplásicos/genética , Fosfolipasas A2 Grupo IV/genética , Concentración de Iones de Hidrógeno , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Espacio Extracelular/metabolismo , Expresión Génica , Silenciador del Gen , Fosfolipasas A2 Grupo IV/metabolismo , Humanos , ARN Interferente Pequeño , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología
19.
Anticancer Res ; 41(1): 237-247, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419818

RESUMEN

BACKGROUND/AIM: Activation-induced cytidine deaminase (AID) is a DNA modifying enzyme which has an essential function in promoting antibody diversification. Its overexpression is strongly associated with B-cell derived malignancies including Burkitt lymphoma, where AID is required for the characteristic c-MYC/IGH translocation. This study aimed at defining AID's oncopathogenic role which is still poorly understood. MATERIALS AND METHODS: We created over-expressing and knock-down cell culture models of AID, and used cellular assays to provide insight into its contribution to lymphomagenesis. RESULTS: We showed that AID expression is highly specific to, and abundantly expressed in B-cell-derived cancers and that ectopic overexpression of AID leads to rapid cell death. Using a knock-down model, we revealed that AID expression significantly impacts genomic stability, proliferation, migration and drug resistance. CONCLUSION: AID is an important driver of lymphoma, impacting multiple cellular events, and is potentially a strong candidate for targeted therapy in lymphoma.


Asunto(s)
Citidina Desaminasa/metabolismo , Resistencia a Antineoplásicos , Linfoma de Células B/metabolismo , Animales , Antineoplásicos/farmacología , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Citidina Desaminasa/genética , Daño del ADN , Doxorrubicina/farmacología , Expresión Génica Ectópica , Activación Enzimática , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/patología
20.
Anticancer Res ; 41(1): 259-268, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419820

RESUMEN

BACKGROUND/AIM: Quinazolinone is a privileged chemical structure employed for targeting various types of cancer. This study aimed to demonstrate the antitumor activity of synthesized 6,7-disubstituted-2-(3-fluorophenyl) quinazolines (HoLu-11 to HoLu-14). MATERIALS AND METHODS: The cytotoxicity was assessed by the sulforhodamine B (SRB) assay. The cell cycle was examined by flow cytometry. The expression levels of cell cycle- and apoptosis-related proteins were estimated by western blotting. A xenograft animal model was used to explore the antitumor effects of HoLu-12. RESULTS: Among four synthetic quinazolinone derivatives, HoLu-12 significantly reduced the viability of oral squamous cell carcinoma (OSCC) cells. HoLu-12 induced G2/M arrest and increased the expression of cyclin B, histone H3 (Ser10) phosphorylation, and cleaved PARP, indicating that HoLu-12 could induce mitotic arrest and then apoptosis. Moreover, the combination of HoLu-12 and 5-fluorouracil (5-FU) displayed synergistic toxic effect on OSCC cells. HoLu-12 significantly inhibited tumor growth in vivo. CONCLUSION: HoLu-12 induces mitotic arrest and leads to apoptosis of OSCC cells. Furthermore, HoLu-12 alone or in combination with 5-FU is a potential therapeutic agent for OSCC.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quinazolinonas/farmacología , Animales , Antineoplásicos/química , Carcinoma de Células Escamosas , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Citometría de Flujo , Fluorouracilo/farmacología , Humanos , Ratones , Mitosis/efectos de los fármacos , Neoplasias de la Boca , Quinazolinonas/química , Ensayos Antitumor por Modelo de Xenoinjerto
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