RESUMEN

Glioblastomas (GBMs), the most common and lethal primary brain tumor, show inherent infiltrative nature and high molecular heterogeneity that make complete surgical resection unfeasible and unresponsive to conventional adjuvant therapy. Due to their fast growth rate even under hypoxic and acidic conditions, GBM cells can conserve the intracellular pH at physiological range by overexpressing membrane-bound carbonic anhydrases (CAs). The synthetic sulfonamide E7070 is a potent inhibitor of CAs that harbors putative anticancer properties; however, this drug has still not been tested in GBMs. The present study aimed to evaluate the effects of E7070 on CA9 and CA12 enzymes in GBM cells as well as in the tumor cell growth, migration, invasion, and resistance to radiotherapy and chemotherapy. We found that E7070 treatment significantly reduced tumor cell growth and increased radio- and chemotherapy efficacy against GBM cells under hypoxia. Our data suggests that E7070 has therapeutic potential as a radio-chemo-sensitizing in drug-resistant GBMs, representing an attractive strategy to improve the adjuvant therapy. We showed that CA9 and CA12 represent potentially valuable therapeutic targets that should be further investigated as useful diagnostic and prognostic biomarkers for GBM tailored therapy.

Asunto(s)

Neoplasias Encefálicas/patología , Inhibidores de Anhidrasa Carbónica/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glioblastoma/patología , Sulfonamidas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Humanos

RESUMEN

BACKGROUND: NF-κB is a transcription factor involved in the transcriptional regulation of a large number of genes related to tumorigenesis in several cancer cell types, and its inhibition has been related to anticancer effect. DHMEQ (Dehydroxymethylepoxyquinomicin) is a compound that blocks the translocation of NF-κB from the cytoplasm to the nucleus, thus inhibiting its activity as a transcriptional activator. Several studies have shown the antineoplastic effects of DHMEQ in numerous tumor types, however, there are no surveys that tested their effects in MB. OBJECTIVES: The aim of the present study was to evaluate the effects of DHMEQ as NF-κB inhibitor in pediatric MB cell lines. METHOD: We used the UW402, UW473 and ONS-76 medulloblastoma (MB) cell lines to verify the effect of DHMEQ on proliferation, clonogenic capacity, apoptosis, cell invasion and migration, and evaluated the effect of the combination with other drugs and the potential as a radiosensitizator. RESULTS: A significant decrease in the cell growth, a strong inhibition of the clonogenic capacity, migration and cell invasion was observed after NF-κB inhibition in the three MB cell lines. Conversely, increased level of apoptosis rates were demonstrated. Additionally, treatments with DHMEQ combined with other chemotherapeutic agents were synergic in most points, and a strong radiosensitization by this compound was observed in the three MB cell lines. CONCLUSION: DHMEQ has potential antitumor effect on MB cells, and it may be considered a new therapeutic agent to improve treatment approaches in MB.

Asunto(s)

Antineoplásicos/farmacología , Benzamidas/farmacología , Ciclohexanonas/farmacología , Meduloblastoma/terapia , FN-kappa B/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclohexanonas/síntesis química , Ciclohexanonas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Meduloblastoma/metabolismo , Estructura Molecular , FN-kappa B/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

Extracellular Vesicles (EVs) are gaining interest as central players in liquid biopsies, with potential applications in diagnosis, prognosis and therapeutic guidance in most pathological conditions. These nanosized particles transmit signals determined by their protein, lipid, nucleic acid and sugar content, and the unique molecular pattern of EVs dictates the type of signal to be transmitted to recipient cells. However, their small sizes and the limited quantities that can usually be obtained from patient-derived samples pose a number of challenges to their isolation, study and characterization. These challenges and some possible options to overcome them are discussed in this review.

Asunto(s)

Vesículas Extracelulares/química , Carbohidratos , Humanos , Lípidos , Ácidos Nucleicos , Pronóstico , Proteínas

RESUMEN

Polo-like kinase 1 (PLK1), a key regulator of mitosis, is often overexpressed in childhood cancers and is associated with poor prognosis. Previous reports have shown that inhibition of PLK1 might serve as a promising anticancer treatment for osteosarcoma. In this study, we tested the second-generation PLK1 inhibitors BI 6727 and GSK461364 in HOS and MG-63 cell lines, both as a single agent and in combination with methotrexate, cisplatin, vinblastine, doxorubicin, or ionizing radiation. Both PLK1 inhibitors worked equally in terms of cell growth arrest, apoptosis induction, and radiosensitization. Combining BI 6727 or GSK461364 with conventional treatments, however, showed trivial synergistic antitumor effects in vitro. Our results reinforce the potential use of PLK1 inhibitors for a pharmacologic intervention in osteosarcoma, although their applicability in polychemotherapeutic regimens deserves further investigation.

Asunto(s)

Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Osteosarcoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Tiofenos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Quinasa Tipo Polo 1

RESUMEN

Cervical adenocarcinoma is one of the most common gynecological malignancies. Despite the improvements in multimodality treatment, advanced disease is still associated with a significantly poor prognosis making the search for more effective therapeutic agents imperative. BI 2536, an unambiguous inhibitor of Polo-like kinase 1 (PLK1), has shown anticancer activity in a variety of tumor cell types. Herein, we present more evidence of the antiproliferative effects of this drug on HeLa cells. Nanomolar concentrations (10-100 nmol/l) of the drug significantly decreased cell proliferation and clonogenic capacity. Our results also demonstrate that inhibition of PLK1 promoted G2/M arrest and resulted in a dramatic increase in the mitotic index after 24 h of treatment. Apoptosis onset was evinced by the accumulation of a sub-G1 population as well as by a significant increase in caspase-3 activity at longer periods of exposure. Taken together, our results reinforce the prospect of directing against PLK1 as a potential therapeutic target to be evaluated in different preclinical models for cervical carcinoma.

Asunto(s)

Antineoplásicos/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/metabolismo , Apoptosis , Ciclo Celular/efectos de los fármacos , Femenino , Células HeLa , Humanos , Quinasa Tipo Polo 1

RESUMEN

Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/ Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 µg/ml DTCM- glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.

Asunto(s)

Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Piperidonas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Apoptosis/efectos de la radiación , Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Western Blotting , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Ensayo de Unidades Formadoras de Colonias , Rayos gamma , Humanos , Necrosis , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/metabolismo

RESUMEN

Osteosarcoma is the most common primary malignant tumor of bone, which frequently occurs in the second decade of life. Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with chemoresistant or metastatic tumors is still poor. Therefore, there is a need for the development of more efficient therapeutic agents. BI 2536, an innovative selective inhibitor of Polo-like kinase 1, has shown anticancer potential promoting mitotic arrest and apoptosis in a variety of tumor cells, including osteosarcoma. Here, we present more evidence of the antiproliferative effects of BI 2536 on HOS and MG-63 osteosarcoma cell lines. Our results showed that nanomolar concentrations (10, 50, and 100 nmol/l) of the drug significantly decreased cell proliferation and clonogenic capacity, inducing mitotic arrest and aneuploidy. Interestingly, although BI 2536 mediated a moderate increase of apoptosis after 48 h in HOS cells, no increased caspase-3 activity was detected for MG-63 cells. In contrast to previous studies, we show that perturbation of normal mitotic progression by BI 2536 in these osteosarcoma cell lines results in caspase-independent mitotic catastrophe followed by necrosis. Our findings reinforce the likelihood of directing against Polo-like kinase 1 as a therapeutic option in the treatment of osteosarcoma.

Asunto(s)

Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/farmacología , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Inestabilidad Cromosómica , Relación Dosis-Respuesta a Droga , Humanos , Mitosis/efectos de los fármacos , Osteosarcoma/genética , Quinasa Tipo Polo 1

RESUMEN

Bladder carcinoma is one of the most common tumors in the world and despite the therapy currently available most of the patients relapse. Better understanding of the factors involved in disease pathogenesis would provide insights for the development of more effective strategies in treatment. Recently, differential miRNA expression profiles in bladder urothelial carcinomas identified miR-100 down-regulation and miR-708 up-regulation among the most common alterations, although the possible influence of these miRNAs in the control of basic mechanisms in bladder tumors has not been addressed. In this context, the present study aimed to evaluate the in vitro effects of miR-100 forced expression and miR-708 inhibition in the bladder carcinoma cell line 5637. Our results showed that overexpression of miR-100 significantly inhibited growth when compared to controls at both times tested (72 and 96 hours, p<0.01) with a maximum effect at 72 hours reducing proliferation in 29.6 %. Conversely, no effects on cell growth were observed after inhibition of miR-708. MiR-100 also reduced colony formation capacity of 5637 cells by 24.4%. No alterations in cell cycle progression or apoptosis induction were observed. The effects of miR-100 on growth and clonogenicity capacity in 5637 cells evince a possible role of this miRNA in bladder carcinoma pathogenesis. Further studies are necessary to corroborate our findings and examine the potential use of this microRNA in future therapeutic interventions.

Asunto(s)

MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Apoptosis/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Transfección , Neoplasias de la Vejiga Urinaria/patología