RESUMEN
Phenotypic screening of α-substituted thiocarbohydrazones revealed promising activity of 1,5-bis(salicylidene)thiocarbohydrazide against leukemia and breast cancer cells. Supplementary cell-based studies indicated an impairment of DNA replication via the ROS-independent pathway. The structural similarity of α-substituted thiocarbohydrazone to previously published thiosemicarbazone catalytic inhibitors targeting the ATP-binding site of human DNA topoisomerase IIα prompted us to investigate the inhibition activity on this target. Thiocarbohydrazone acted as a catalytic inhibitor and did not intercalate the DNA molecule, which validated their engagement with this cancer target. A comprehensive computational assessment of molecular recognition for a selected thiosemicarbazone and thiocarbohydrazone provided useful information for further optimization of this discovered lead compound for chemotherapeutic anticancer drug discovery.
RESUMEN
Anticancer activity of Pd complexes 1-5 with bidentate N-heteroaromatic hydrazone ligands was investigated on human acute monocytic leukemia (THP-1; cells in a suspension) and human mammary adenocarcinoma (MCF-7; two-dimensional layer and three-dimensional spheroid tumor model) cell lines. For the Pd(II) complexes with condensation products of ethyl hydrazainoacetate and quinoline-8-carboxaldehyde (complex 1) and 2-formylpyridine (complex 3), for which apoptosis was determined as a mechanism of anticancer activity, further investigation revealed that they arrest the cell cycle in G0/G1 phase, induce generation of reactive oxygen species and inhibit Topoisomerase I in vitro. In silico studies corroborate experimental findings that these complexes show topoisomerase inhibition activity in the micromolar range and indicate binding to a DNA's minor groove as another potential target. Based on the results obtained by circular dichroism and fluorescence spectroscopy measurements, the most active complexes are suitable to be delivered to a blood stream via human serum albumin.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Daño del ADN/efectos de los fármacos , Hidrazonas/química , Paladio/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Unión Proteica , Albúmina Sérica Humana/metabolismo , Relación Estructura-Actividad , Células THP-1RESUMEN
Cardiotoxicity is one of the main limiting side effects of doxorubicin and cyclophosphamide (DC) treatment, and this study was organized to identify cardioprotective activity of amifostine and dexrazoxane against DC combination. BalbC/NIH mice underwent DC treatment (DC group), were pre-treated with amifostine (ADC group) or dexrazoxane (IDC group) and were killed at 1.5 and 3 months after treatments when the grade of myocardial damage was analysed by light microscopy using the Billingham scoring method. DC treatment induced severe myocardial damage with one lethal event before evaluation at 3 months. Main characteristics of DC cardiotoxicity were polymorphic myocyte degeneration and alterations in blood vessels followed by ecchymoses, haemorrhage and thromboses. Polymorphism was also found in the IDC and ADC groups, but its morphological patterns were different. In animals subject to IDC treatment, the blood vessels were better preserved than in the ADC group, whereas thrombosis was not seen in either of these two groups. Quantitatively, grade of myocardial injury in the ADC and IDC groups was significantly higher compared with the non-treated group at both times of estimation and significantly lower compared with the DC group at 1.5 months. At 3 months, significance against DC treatment was lost in the ADC group, while preserved in the IDC-treated animals. Also, there was significant progression in the ADC group comparing scores between 1.5 and 3 months. These results revealed that the cardiotoxicity of DC combination displays specific morphological hallmark and evolution in time, different to those described after doxorubicin single treatment. Neither amifostine nor dexrazoxane prevented development of cardiomyopathy induced by DC treatment.
Asunto(s)
Amifostina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/prevención & control , Dexrazoxano/farmacología , Animales , Cardiomiopatías/inducido químicamente , Cardiotónicos/farmacología , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Combinación de Medicamentos , Femenino , Ratones , Ratones Endogámicos BALB C , Miocardio/patologíaRESUMEN
Novel complexes of platinum(II) with 3- (1) or 4-acetylpyridine (2) have been synthesized and characterized by elemental analyses, IR, (1)H and (13)C NMR spectroscopy. Single crystal X-ray diffraction revealed the trans geometry of complex 2. DFT calculations confirm formation of trans isomers for both complexes. The complexes have been tested for their cytotoxicity against HeLa (human cervical cancer), U2OS (human osteosarcoma), U2OScisR (human osteosarcoma cisplatin resistant), B16 (murine melanoma), MDA-453, MDA-361, and MCF-7 (human breast cancer), LS-174 (human colon cancer) and FemX (human melanoma) cell lines. The most promising compound trans-dichloridobis(4-acetylpyridine)platinum(II) (2) overcomes cisplatin resistance of U2OScisR cells after 48h of drug exposure.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Platino/síntesis química , Piridinas/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Compuestos de Platino/farmacología , Piridinas/farmacología , Análisis Espectral , Relación Estructura-ActividadRESUMEN
Treatment options for metastatic renal cell carcinoma (RCC) have been limited due to its resistance to chemotherapy and radiotherapy. Benefits from immunotherapeutic agents provide only a small subset of patients. During the past decade major advances have been made toward understanding the molecular basis of RCC development. Such acquired knowledge has offered unique opportunities for the development of molecular targeting agents. These agents are predominately small molecules or monoclonal antibodies that exert their action through modulation of protein activity or inhibition of amplified signals directly implicated in disease mechanism. To date, some of newly molecular targeted agents have entered advanced phases of clinical development, received marketing authorization by regulatory agencies and have opened a possibility of multiple treatment options. This article overviews current knowledge in RCC molecular pathology with recent clinical data, and discuss present strategies for future development of targeted therapies.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/patología , Ensayos Clínicos como Asunto , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Humanos , Neoplasias Renales/patologíaRESUMEN
Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Bencenosulfonatos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Sirolimus/análogos & derivados , Inhibidores de la Angiogénesis/farmacología , Bencenosulfonatos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Resistencia a Antineoplásicos , Everolimus , Humanos , Indoles/farmacología , Neoplasias Renales/enzimología , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Niacinamida/análogos & derivados , Selección de Paciente , Compuestos de Fenilurea , Guías de Práctica Clínica como Asunto , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Piridinas/farmacología , Pirroles/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Sirolimus/farmacología , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Serina-Treonina Quinasas TOR , Resultado del TratamientoRESUMEN
Doxorubicin is one of the most active drugs in oncology, with cardiotoxicity as a serious side effect of its application. The aim of this study was to investigate dexrazoxane and amifostine impact on the evolution of myocardial changes induced by doxorubicin. BalbC female mice were treated with doxorubicin only (10 mg/kg, single intravenous push), or with dexrazoxane (200 mg/kg, intraperitoneal [ip]) or amifostine (200 mg/kg, ip) 60 mins or 30 mins prior to treatment with doxorubicin, respectively. Blood sampling for determination of conventional serum-marker activity was performed 48 hrs later. The grade of histopathology changes was evaluated by light microscopy 1.5 and 3 months after treatments using the Billingham scoring method. Control groups consisted of nontreated mice. After doxorubicin-only treatment, the grade of heart tissue damage was found to increase in the period between 1.5 and 3 months. A similar but less intense progression was also detected in amifostine-pretreated animals, with significant difference among median Billingham scores between the two time points. The pretreatment with dexrazoxane suspended expansion of tissue lesions in time. Changes in serum enzyme activity revealed two correlations: the greater reduction in alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) leakage is associated with a lower percentage of damaged tissue, and the creatine kinase to alpha-HBDH percent of difference ratio being greater than one is correlated with limited spreading of pathological lesions. Our results indicate that the development of doxorubicin-induced heart failure is based on a slow and persistent expansion of pathological process even long after the completion of the treatment. Dexrazoxane has proved to be successful and superior over amifostine against such an evolution of doxorubicin cardiomyopathy.
Asunto(s)
Amifostina/farmacología , Antibióticos Antineoplásicos/efectos adversos , Cardiomiopatías , Fármacos Cardiovasculares/farmacología , Doxorrubicina/efectos adversos , Protectores contra Radiación/farmacología , Razoxano/farmacología , Animales , Antibióticos Antineoplásicos/farmacología , Cardiomiopatías/inducido químicamente , Cardiomiopatías/enzimología , Cardiomiopatías/patología , Cardiomiopatías/prevención & control , Creatina Quinasa , Doxorrubicina/farmacología , Femenino , Hidroxibutirato Deshidrogenasa/sangre , Ratones , Ratones Endogámicos BALB C , Miocardio/enzimología , Miocardio/patología , Factores de TiempoRESUMEN
The aim of this study was to investigate the cardioprotective activity of vitamin E against doxorubicin alone and doxorubicin in combination with cyclophosphamide in mice. Female BalbC/NIH mice were treated with vitamin E (100 IU/kg, orally) 24 hr before single bolus doses of doxorubicin (10 mg/kg, intravenously), or doxorubicin and cyclophosphamide (150 mg/kg, intraperitoneally). Non-treated animals served as negative controls, while positive control groups received doxorubicin or doxorubicin and cyclophosphamide. For evaluation, serum enzyme activity of aspartate aminotransferase (AST), lactate dehidrogenase (LDH), alpha-hydroxybutirate dehydrogenase (alpha-HBDH), and creatine kinase (CK) at 48 hr and histopathology examination of the heart tissue (Billigham rules) at 1.5 and 3 months followed to treatments were used. In sera of mice treated with vitamin E prior to doxorubicin, the creatine kinase and % alpha-HBDH activity were significantly reduced, compared to positive control. Histopathology changes (scored as 1.5 at 1.5 and 3 months respectively) were not significant compared to negative control at both time points of examination. In animals which received vitamin E before doxorubicin and cyclophosphamide, none of the serum enzymes was significantly reduced compared to positive control, but non-significant increase in AST and creatine kinase activity was detected (3% and 16.57% respectively). The degree of myocardial damage was significantly higher compared to non-treated group (2.0 and 2.5 at 1.5 and 3 months respectively). Current results show that vitamin E in single oral dose failed to inhibit acute cardiotoxic activity of doxorubicin, but suspended further progression of the heart muscle damage over the time. On the contrary, vitamin E did not attain any cardioprotection against doxorubicin and cyclophosphamide in combination.