Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes / Drug repositioning for oral cancer: Identifying candidate therapeutic agents

Objetivos: O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como...

Objectives: Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents.

Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes / Drug repositioning for oral cancer: Identifying candidate therapeutic agents

O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como...

Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents...

Histological study on the effect of heat stress on cardiac muscle of adult male albino rats and the possible role of mast cells

Heat stress causes serious physiological dysfunction that may result in heat related diseases. The cardiovascular system has been considered the primary target of heart stress. The mechanism of heat stress- induced myocardial damage remains unclear. Recent findings indicate that mast cells are not only necessary for allergic reaction, but they also involved in a variety of neuro inflammatory diseases especially those worsened by stress. This work was aimed to study the effect of heat stress on the myocardium of rats and to clarify the possible role of mast cells in this process. This study was performed on 30 adult male albino rats, divided into three equal main groups [10 rats/ each]; the first main group was control, divided into two equal subgroups [5 rats/ each], the first subgroup [A] was negative control, the second subgroup [B] received 1 ml sterile saline I.P daily for 15 days. The second main group was heat-stressed group which was exposed to heat stress [39°C for 2 hours daily] and the third main group was mast cell stabilized group that received 10 mg/kg/b.w of doxantrazole followed by exposure to heat stress [the same as the second main group], half an hour after drug intake. All rats were sacrificed after 15 days and heart sections were processed. Paraffin sections were stained with H and E, masson trichrom [M.T] and toluidine blue for histological study. Other sections were processed for immuno histochemical demonstration of actin and caspase- 3. Other very small pieces of heart sections were processed for electron microscopic study [E.M]. The cardiac muscle of stressed second group revealed focal areas of necrosis, areas of vaculations with loss of characteristic striations and mononuclear cell infiltration. Congestion and extravasation of blood with odema fluid between cardiac muscle fibers were evident. Excessive collagen fibers deposition was also seen. Decreased reaction for actin and strong+ve reaction for caspase-3 in the affected fibers were demonstrated. Moreover hyperplasia and activation with degranulation of mast cells were documented in C.T endomesium. On ultrastructural level, the same group showed disorganized and fragmented microfilaments and mitochondrial changes. Moreover, degranulated mast cells were documented in the C.T endomesium. On the other hand, non of these changes were observed in cardiac muscles of mast cell stabilized group with the exception of slight congestion and minimal fibrosis in the interstitium and perivascular areas at light microscopic level. It is concluded that heat stress induced histological and ultra structural changes in myocardium and these changes could be mast cell mediated. Such study provided further support for the role of mast cells in stress induced myocardial damage and therefore it might provide a novel medical strategy and therapeutic target in management of heat stress induced cardiomyopathy. Furthermore, stress exposure should be avoided or minimized as much as possible to seek for good health

Role of mucosal mast cells in visceral hypersensitivity in a rat model of irritable bowel syndrome

The involvement of mucosal mast cells (MMC) in the pathophysiology of irritable bowel syndrome (IBS) is still controversial. We aimed to re-evaluate the role of MMC in visceral hypersensitivity associated with IBS using a rat IBS model that develops the IBS symptom after a subsidence of acetic acid-induced colitis. No significant difference in the number of MMC was observed between normal rat colon and IBS rat colon. (61.7 +/-2.9/mm 2 in normal vs. 88.7 +/-13.3/mm 2 in IBS, p >0.29). However, the degranulation rate of MMC was significantly higher in IBS rat colon (49.5 +/-2.4% in normal vs. 68.8 +/-3.4% in IBS, p >0.05). Pretreatment of a mast cell stabilizer, doxantrazole (5 mg/kg, i.p.), reduced the degranulation rate of MMC and significantly attenuated visceral hypersensitivity to rectal distension in IBS rat, whereas it had no effect on the visceral sensory responses in normal rat. These results suggest that, although the number of MMC is not significantly changed in IBS rat colon, the higher degranulation rate of MMC is responsible for visceral hypersensitivity in this model IBS.

Progress in researches on drugs for prostate cancer / 中华男科学杂志

In the recent years, researches on drugs for prostate cancer have received more attention than ever before. This article reviews the mechanism and efficacy of such prostate cancer drugs as bicalutamide, medroxyprogesterone acetate, megestrol acetate, flutamide and so on, as well as the clinical data and clinical uses of calcitriol analogue EB1089, SR233377, etc.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

Citoprotección gástrica por cromoglicato disódico y RS-7540 / Gastric cytoprotection by disodium chromoglycate and RS-7540

Se estudió el efecto de la droga RS-7540 sobre la secreción gástrica en ratas sometidas a ligadura del piloro por una hora. Se comparó, con la utilización de dosis equimolares (2,0. 10 mol/kg) la acción del CGDS con li de la droga RS-7540 en el modelo de inducción de lesiones por etanol al 96% Se encontró que la droga RS-7540 no inhibió significativamente el volumen ni la acidez de la secreción gástrica y protegió la mucosa gástrica de las lesiones inducidas por etanol al 96%, por lo que tiene un efecto citoprotector. No existen diferencias significativas sobre el efecto citoprotector de la droga RS-7540 y del cromoglicato disódico. La administración simultánea de ambas drogas no aumenta la protección de la mucosa gástrica

Flupenthixol decanoate [fluanxol depot] in the treatment of chronic schizophrenic patients

Flupenthixol Decanoate was used for the maintenance treatment of 15 chronic schizophrenics. All the patients had been on a variety of neuroleptics before entering the trial. During the trial almost all the patients received injections of 40mg Flupenthixol Depot with interval of 2 weeks. Patients were assessed on Hamilton rating scale for depression, the clinical global impression scale, the brief psychiatric rating scale and a side effect checklist. The trial showed Flupenthixol to be an effective anti-psychotic in the treatment of chronic schizophrenics

Value of etrenol in the periodic treatment of bilharziasis in Iraq

Sequential treatment was given to 285 school children at a dose of 3.0 mg/kg body weight. Re-examination was carried out at three months post-treatment and those still positive were scheduled for re-treatment. The cumulative cure rate 15 months after the first treatment was 95%. The average number of injections per cure was two. Prevalence in school children was reduced from 14.6% to 3.9% in the presence of an active transmission rate of 12%, based on children originally negative but converted to positive during the year

Gastric responses to flupenthixol, a new thioxanthene derivative in rats.

Flupenthixol, a new thioxanthene derivative, was studied for its effects on gastric secretion and gastric ulcers in rats. The compound diminished the volume of gastric secretion, decreased total acid output and protected the glandular gastric mucosa. The observations may be of clinical significance.