RESUMO
INTRODUCTION AND IMPORTANCE: Purtscher retinopathy is the rare form of occlusive microvasculopathy, characterized by multiple retinal white areas around the optic nerve head and fovea with paravascular clearing and may be related to intraretinal hemorrhages. Acute Pancreatitis (AP) is one of the most common gastrointestinal reasons for hospital admissions globally. The complications of Acute Pancreatitis may include Purtscher's-like retinopathy, which has a low incidence rate of less than 0.24 instances per million cases. This case report highlights the value of thorough medical history taking and examination, and it apprises the consideration of ophthalmological manifestation in patients of Acute Pancreatitis. CASE PRESENTATION: A 34-year-old female came to the emergency room due to intense abdominal pain associated with nausea and vomiting, which worsened over the last 24 h. The pain was described as continuous, sharp, and cramping-like in the upper abdomen, radiating to the back. Lab tests revealed elevated serum amylase and lipase levels, indicating pancreatitis, along with slight leukocytosis. A contrast-enhanced CT scan confirmed acute pancreatitis with mild inflammation and enlargement of the pancreas. Two days after admission, the patient experienced a sudden and painless loss of central vision in both eyes. There was no history of trauma or any other significant relevant history, other than pancreatitis. The ophthalmologist's examination found reduced visual acuity (6/60 in the right eye, 3/60 in the left eye), normal corneas, and anterior chambers. DISCUSSION: Inkeles and Walsh established the first link between acute pancreatitis and Purtscher-like retinopathy when they reported three cases of the distinctive retinal appearance in individuals with acute pancreatitis in 1975. CONCLUSION: The recovery and prognosis in cases of Purtscher-like retinopathy is variable and further research is required to ascertain the usage of corticosteroids and pentoxifylline in improving the course of a patient's with Purtscher's-like retinopathy.
RESUMO
Rigosertib is a styryl benzyl sulfone that inhibits growth of tumor cells and acts as a RAS mimetic by binding to Ras binding domains of RAS effectors. A recent study attributed rigosertib's mechanism of action to microtubule binding. In that study, rigosertib was obtained from a commercial vendor. We compared the purity of clinical-grade and commercially sourced rigosertib and found that commercially sourced rigosertib contains approximately 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical-grade rigosertib, which is free of this impurity, does not exhibit tubulin-binding activity. Cell lines expressing mutant ß-tubulin have also been reported to be resistant to rigosertib. However, our study showed that these cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Rigosertib induced a senescence-like phenotype in the small percentage of surviving cells, which could be incorrectly scored as resistant using short-term cultures.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Glicina/análogos & derivados , Neoplasias Pulmonares/patologia , Sulfonas/farmacologia , Tubulina (Proteína)/metabolismo , Contaminação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Glicina/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Mutação , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Células Tumorais CultivadasRESUMO
ZnO/V2O5 nanocomposite thin films were synthesised by the spray pyrolysis technique with optimised deposition parameters by varying the concentration of vanadium pentoxide. The X-ray diffraction results showed that the ZnO/V2O5 nanocomposite thin films have a Wurtzite-type hexagonal ZnO structure. We attained crystal phases at all concentrations. These results indicated that the two crystal phases of pure zinc oxide and vanadium pentoxide exist together within the composite thin film matrix. The morphology was investigated with field emission scanning electron microscopy and transmission electron microscopy (TEM). The microstructures of the deposited thin films were confirmed by Raman spectroscopy. The optical characterizations of the prepared samples were investigated by using a UV-vis spectrophotometer. X-ray photoelectron spectroscopy (XPS) was carried out to confirm the oxidation states of the elements existing on the surface of the composite thin films. The gas-sensing properties of the composite thin films towards toluene gas were studied at the temperature of 27 °C. The sensing mechanism for toluene gas was reported; the response and recovery times were determined from the transient response curve and were found to be 24 s and 28 s, respectively, for the optimised composite film.
RESUMO
Heterostructures developed using CeO2 show promising peculiarities in the field of metal oxide gas sensors due to the great variations in the resistance during the adsorption and desorption processes. NiO decorated CeO2 nanostructures (NiO/CeO2) were synthesized via a facile two-step process. High resolution transmission electron microscopy (HRTEM) results revealed the perfect decoration of NiO on the CeO2 surface. The porous nature of the NiO/CeO2 sensor surface was confirmed from scanning electron microscopy (SEM) analysis. Gas sensing studies of pristine CeO2 and NiO/CeO2 sensors were performed under room conditions and enhanced gas sensing properties for the NiO/CeO2 sensor towards isopropanol were observed. Decoration of NiO on the CeO2 surface develops a built-in potential at the interface of NiO and CeO2 which played a vital role in the superior sensing performance of the NiO/CeO2 sensor. Sharp response and recovery times (15 s/19 s) were observed for the NiO/CeO2 sensor towards 100 ppm isopropanol at room temperature. Long-term stability of the NiO/CeO2 sensor was also studied and discussed. From all the results it is concluded that the decoration of NiO on the CeO2 surface could significantly enhance the sensing performance and it has great advantages in designing best performing isopropanol gas sensors.
RESUMO
Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling.
Assuntos
Glicina/análogos & derivados , Proteínas de Ligação a RNA/química , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Sequência de Aminoácidos , Animais , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Cristalografia por Raios X , Dimerização , Glicina/administração & dosagem , Glicina/química , Glicina/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Neoplasias Pancreáticas/tratamento farmacológico , Fosforilação , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Sulfonas/administração & dosagem , Sulfonas/química , Proteínas ras/metabolismo , Quinase 1 Polo-LikeRESUMO
Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma.
Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/fisiologia , Perfilação da Expressão Gênica , Humanos , Camundongos , Mieloma Múltiplo/patologia , Proteínas Quinases/fisiologia , Proteínas Repressoras/fisiologia , Sirtuína 1/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.
Assuntos
Descoberta de Drogas , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinonas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
Heat shock protein (Hsp) 90 is a key component of the super-chaperone complex that maintains functionally active conformation of various client proteins. Many of these client proteins regulate important nodal points in multiple signalling pathways that promote cancer cell growth and survival. Inhibitors of Hsp90, therefore, have the potential of functioning as anti-cancer agents with pleiotropic effects. Identification of novel Hsp90 inhibitors with more favourable pharmacological properties is a priority in cancer therapy. To achieve this goal, we screened a compound library using a biochemical assay based on refolding of denatured firefly luciferase. The assay revealed high sensitivity, reliability and reproducibility with a Z-factor of 0.81 ± 0.17. Six Hsp90 inhibitory compounds identified by this screening with IC50 values between 1.0 and 6 µM were further characterised for anti-proliferative activity by Cell Titer-Blue Cell Viability Assay using multiple tumour cell lines. Of particular interest was ONO4140 with lowest GI50 values in three different cancer cell lines viz; DU-145, BT-474 and K562 cell lines. This study also revealed that short-term exposure of tumour cells with ONO4140 is sufficient to inhibit the catalytic activity of Hsp90, evaluated through disruption of Hsp90-p23 association by immunoprecipitation. This short term exposure appears to initiate events like degradation of Hsp90 client proteins such as ErbB2/Her-2 and Akt with concomitant inhibition of survival signalling leading to the apoptotic death of tumour cells as seen by western blotting and Caspase Glow-3,7 assay. The study also reveals that apoptosis following Hsp90 inhibition with ONO4140 occurs via Caspase9-Caspase3 intrinsic apoptotic pathway, a process that is likely triggered by inactivation of Akt. In conclusion, we have identified a novel class of synthetic compounds which show potent Hsp90 inhibitory action in preclinical studies. The discovery of this novel class of synthetic Hsp90 inhibitors with simple chemical backbone allows us to conduct further structural modifications to improve their potency and pharmacokinetic properties for use in cancer therapy.
Assuntos
Chalconas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Sulfonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células K562 , Luciferases de Vaga-Lume/química , Luciferases de Vaga-Lume/metabolismo , Coelhos , Transdução de SinaisRESUMO
The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication, and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the hematopoietic stem cell (HSC) pool, leading to profound reductions in mature lymphoid, erythroid, and myeloid cells. This defect is autonomous to the bone marrow and is first evident in stem cells, which accumulate in the S and G2/M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment, consisting of depletion of common myeloid progenitors but relative sparing of granulocyte-macrophage progenitors. Microarray studies indicate that B-myb-null LSK(+) cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/fisiologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Células Progenitoras Mieloides/fisiologia , Transativadores/metabolismo , Animais , Transplante de Medula Óssea , Cruzamentos Genéticos , Primers do DNA/genética , Citometria de Fluxo , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
ON123300 is a low molecular weight multikinase inhibitor identified through a series of screens that supported further analyses for brain tumor chemotherapy. Biochemical assays indicated that ON123300 was a strong inhibitor of Ark5 and CDK4, as well as growth factor receptor tyrosine kinases such as ß-type platelet-derived growth factor receptor (PDGFRß). ON123300 inhibited U87 glioma cell proliferation with an IC(50) 3.4 ± 0.1 µmol/L and reduced phosphorylation of Akt, yet it also unexpectedly induced Erk activation, both in a dose- and time-dependent manner that subsequently was attributed to relieving Akt-mediated C-Raf S259 inactivation and activating a p70S6K-initiated PI3K-negative feedback loop. Cotreatment with the EGFR inhibitor gefitinib produced synergistic cytotoxic effects. Pursuant to the in vitro studies, in vivo pharmacokinetic and pharmacodynamic studies of ON123300 were completed in mice bearing intracerebral U87 tumors following intravenous doses of 5 and 25 mg/kg alone, and also at the higher dose concurrently with gefitinib. ON123300 showed high brain and brain tumor accumulation based on brain partition coefficient values of at least 2.5. Consistent with the in vitro studies, single agent ON123300 caused a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors, whereas addition of gefitinib to the ON123300 regimen significantly enhanced p-Akt inhibition and prevented Erk activation. In summary, ON123300 demonstrated favorable pharmacokinetic characteristics, and future development for brain tumor therapy would require use of combinations, such as gefitinib, that mitigate its Erk activation and enhance its activity.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/administração & dosagem , Piridonas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
Assuntos
Antineoplásicos/síntese química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Piridinas/síntese química , Pirimidinas/síntese química , Proteínas Repressoras/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Proteínas Quinases , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6'-trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HCT116 , Humanos , Células K562 , Células MCF-7 , Camundongos , Camundongos Nus , Microtúbulos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Polimerização/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Tubulina (Proteína)/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
Development of radio-protective agents that are non-toxic is critical in light of ever increasing threats associated with proliferation of nuclear materials, terrorism and occupational risks associated with medical and space exploration. In this communication, we describe the discovery, characterization and mechanism of action of ON01210.Na, which effectively protects mouse and human bone marrow cells from radiation-induced damage both in vitro and in vivo. Our results show that treatment of normal fibroblasts with ON01210.Na before and after exposure to ionizing radiation provides dose dependent protection against radiation-induced damage. Treatment of mice with ON01210.Na prior to radiation exposure was found to result in a more rapid recovery of their hematopoietic system. The mechanistic studies described here show that ON01210.Na manifests its protective effects through the up-regulation of PI3-Kinase/AKT pathways in cells exposed to radiation. These results suggest that ON 01210.Na is a safe and effective radioprotectant and could be a novel agent for use in radiobiological disasters.
Assuntos
Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Protetores contra Radiação/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Sulfonamidas/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos , Bibliotecas de Moléculas PequenasRESUMO
A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations have failed. The scope of this reaction was successfully extended for the synthesis of (E)-ON 01910·Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910·Na. It is interesting to note that all the E-isomers synthesized have shown better cytotoxicity profile on cancer cells compared to the Z-isomers.
Assuntos
Alcinos/farmacologia , Antineoplásicos/farmacologia , Glicina/análogos & derivados , Compostos de Sulfidrila/química , Sulfonas/farmacologia , Alcinos/síntese química , Alcinos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Células K562 , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/químicaRESUMO
PURPOSE: Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma, and new therapeutic strategies are urgently needed. EXPERIMENTAL DESIGN: The effects of ON 013105, a novel benzylstyryl sulfone kinase inhibitor, alone or with doxorubicin or rituximab, were examined in Granta 519 and Z138C cells. For in vivo studies, CB17/SCID mice were implanted subcutaneously with Z138C cells and treated with various combinations of ON 013105, doxorubicin, and rituximab. Tumor burden and body weight were monitored for 28 days. RESULTS: ON 013105 induced mitochondria-mediated apoptosis in MCL cells. Death was preceded by translocation of tBid to the mitochondria and cytochrome c release. In addition, ON 013105-treated cells exhibited reduced levels of cyclin D1, c-Myc, Mcl-1, and Bcl-xL. Using nuclear magnetic resonance (NMR) spectroscopy, we showed specific binding of ON 013105 to eIF4E, a critical factor for the initiation of protein translation. We proffer that this drug-protein interaction preferentially prevents the translation of the aforementioned proteins and may be the mechanism by which ON 013105 induces apoptosis in MCL cells. Efficacy studies in a mouse xenograft model showed that ON 013105 inhibited MCL tumor growth and that combining ON 013105 with rituximab reduced tumor burden further with negligible unwanted effects. CONCLUSIONS: Our findings suggest that ON 013105, alone or in combination with rituximab, may be a potent therapeutic agent to treat MCLs.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Estirenos/administração & dosagem , Sulfonas/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Fator de Iniciação 4E em Eucariotos/metabolismo , Feminino , Expressão Gênica , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rituximab , Estirenos/metabolismo , Estirenos/farmacocinética , Sulfonas/metabolismo , Sulfonas/farmacocinéticaRESUMO
ON 013100, (E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone, is a potent kinase inhibitor whose phosphate form is in Phase I clinical trials in lymphoma and acute lymphoid leukemia. The objectives were to: (a) investigate the possible presence of the glucuronide metabolite of the drug in two representative colon cancer cell lines, a drug resistant (colo-205) and a drug sensitive (colo-320); (b) quantify the glucuronide metabolite and the unchanged drug in the cells after treatment with ON 013100. The glucuronide was synthesized and a selective LC/MS/MS method was developed and validated for the characterization and quantification of the metabolite. The glucuronide metabolite (570.6 Da) was found in the drug-resistant cells upon a 1h incubation with ON 013100 (20 µg/ml). After treatment with the drug, the concentration of the metabolite gradually decreased from 0.84 µg/ml at 0 h through 0.21 µg/ml at 6h to below detection limit of 8.0 ng/ml at 9 h. No glucuronide metabolite was detected in the drug-sensitive cells. The concentrations of intact ON 013100 in the drug-resistant cells gradually decreased from 0.41 µg/ml (0 h) to 0.06 µg/ml (9 h). The corresponding concentrations of the intact drug in the drug-sensitive cells were from 2.88 µg/ml to 0.94 µg/ml.
Assuntos
Antineoplásicos/metabolismo , Compostos de Benzil/metabolismo , Neoplasias do Colo/metabolismo , Glucuronídeos/análise , Inibidores de Proteínas Quinases/metabolismo , Estirenos/metabolismo , Antineoplásicos/análise , Antineoplásicos/farmacologia , Compostos de Benzil/análise , Compostos de Benzil/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Glucuronídeos/química , Glucuronídeos/metabolismo , Humanos , Cinética , Limite de Detecção , Desintoxicação Metabólica Fase I , Peso Molecular , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Estirenos/análise , Estirenos/farmacologia , Sulfonas , Espectrometria de Massas em TandemRESUMO
The goal of the study was to develop an effective screening strategy to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON123x] by the combined use of in silico, in vitro cytotoxicity, and in vitro ADME profiling studies. The results of these studies were cast into a pipeline of tier 1 and tier 2 procedures that resulted in the identification of ON123300 as the lead compound. Of the 154 ON123xx compounds, 13 met tier 1 screening criteria based on physicochemical properties [i.e., MW < 450 Da, predicted log P between 2 and 3.5] and in vitro glioma cell cytotoxicity [i.e., IC50 < 10 µM] and were further tested in tier 2 assays. The tier 2 profiling studies consisted of metabolic stability, MDCK-MDR1 cell permeability and plasma and brain protein binding that were combined to globally assess whether favorable pharmacokinetic properties and brain penetration could be achieved in vivo. In vivo cassette dosing studies were conducted in mice for 12 compounds that permitted examination of in vitro/in vivo relationships that confirmed the suitability of the in vitro assays. A parameter derived from the in vitro assays accurately predicted the extent of drug accumulation in the brain based on the area under the drug concentration-time curve in brain measured in the cassette dosing study (r (2) = 0.920). Overall, the current studies demonstrated the value of an integrated pharmacokinetic-driven approach to identify potentially efficacious agents for brain tumor chemotherapy.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas , Animais , Antineoplásicos/uso terapêutico , Barreira Hematoencefálica , Encéfalo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ligação ProteicaRESUMO
PURPOSE: To evaluate a mitotic inhibitor, ON01910.Na, as a potential chemotherapeutic agent for brain tumors using a series of PK/PD studies, which led to the evaluation of its structural analog, ON013105, a prodrug of the more lipophilic product, ON013100. METHODS: Systemic PK characterization of ON01910 and ON013105 was completed in healthy mice. Using an orthotopic U87 glioma mouse model, brain and brain tumor distribution under steady-state conditions were evaluated for ON01910.Na and ON013105/ON013100; anticancer potential following a multiple-dose schedule of 250 mg/kg/day IP for 7 days was evaluated for ON01910.Na. RESULTS: ON01910 exhibited low brain and brain tumor distribution with quasi-steady-state brain/plasma (Css(brain)/Css(plasma)) and brain tumor/plasma (Css(brain tumor)/Css(plasma)) concentration ratios of 0.03 ± 0.02 and 0.14 ± 0.08, respectively. Significant antiangiogenic potential and antiproliferative capacity of ON01910 in the intracerebral model was absent. ON013100 showed high brain and brain tumor penetration with Css(brain)/Css(plasma) and Css(brain tumor)/Css(plasma) ratios of 0.92 ± 0.26 and 1.35 ± 0.40, respectively; its prodrug ON013105 showed negligible brain and brain tumor penetration. CONCLUSIONS: ON013105, not ON01910.Na, was identified as a potential anticancer drug candidate for further investigation in brain tumor chemotherapy based on the properties of ON013100.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Cromatografia Líquida , Avaliação Pré-Clínica de Medicamentos , Camundongos , Espectrometria de Massas em TandemRESUMO
Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. A series of (Z)-1-aryl-3-arylamino-2-propen-1-one (10) were synthesized and evaluated for antiproliferative activity in cell-based assay. The most active compound (Z)-1-(2-bromo-3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenylamino)prop-2-en-1-one (10ae) was tested in 20 tumor cell lines including multidrug resistant phenotype and was found to induce apoptosis in all these cell lines with similar GI(50) values. Flow cytometry studies showed that 10ae arrested the cells in G2/M phase of cell cycle. In addition to G2/M block, these compounds caused microtubule stabilization like paclitaxel and induced apoptosis via activation of the caspase family. The observations made in this investigation demonstrate that (Z)-1-Aryl-3-arylamino-2-propen-1-one (10) represents a new class of microtubule-stabilizing agents.
Assuntos
Alcenos/síntese química , Aminofenóis/síntese química , Antineoplásicos/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/metabolismo , Alcenos/química , Alcenos/farmacologia , Aminofenóis/química , Aminofenóis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Polimerização , Fuso Acromático/efeitos dos fármacos , Fuso Acromático/ultraestrutura , Estereoisomerismo , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico, in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of > 450 Da, a predicted log P (log P) of either <2 or > 3.5, and a cytotoxicity IC(50) value of > 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood-brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570's resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy.