ABSTRACT
Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.
Subject(s)
Humans , Sirolimus/pharmacology , Dichloroacetic Acid/pharmacology , Pyruvate Dehydrogenase Complex , TOR Serine-Threonine Kinases , Mechanistic Target of Rapamycin Complex 1 , Neoplasms/drug therapyABSTRACT
Introdução: A cirurgia micrográfica de Mohs é empregada para exérese de neoplasias cutâneas, especialmente carcinomas basocelulares de subtipos histológicos localmente agressivos, tumores recidivados ou localizados em regiões nobres. Apresenta elevados índices de cura e permite preservação tecidual. O objetivo é analisar a eficácia da cirurgia micrografia de Mohs e os métodos de reconstrução utilizados. Método: Foram coletados, retrospectivamente, dados de 50 pacientes submetidos à exérese de tumores cutâneos por meio da cirurgia micrográfica de Mohs e à reconstrução da perda de substância. Todos os pacientes foram operados no período entre janeiro de 2005 a dezembro de 2013 na Clínica de Cirurgia Plástica do Hospital Felício Rocho (Belo Horizonte, MG, Brasil). Os pacientes foram estudados com relação à idade, gênero, localização do tumor, tratamento prévio, tipo histológico, número de fragmentos analisados na cirurgia micrográfica, método de reconstrução empregado e proservação. Resultados: Trinta e um pacientes (62%) foram do gênero feminino e 19 (38%) do masculino. A média de idade foi de 63,8 anos. Todas as lesões encontravam-se na face, com 66% dos casos com acometimento da região nasal. Considerando o diagnóstico pré-operatório, 48 casos (96%) eram carcinoma basocelulares e dois casos (4%) correspondiam ao carcinoma microcístico anexial. Retalhos locais foram o tipo de reconstrução mais utilizado. Os pacientes foram acompanhados por média de 48,4 meses. Nenhum caso de recidiva tumoral foi observado. Conclusão: A cirurgia micrográfica de Mohs se mostrou altamente eficaz no tratamento dos 50 casos de neoplasias cutâneas. Recomenda-se que os defeitos cirúrgicos sejam reparados pelo cirurgião plástico.
Introduction: Mohs micrographic surgery is used for the excision of skin neoplasms, especially in locally aggressive histological subtypes of basal cell carcinoma, tumor recurrences, or tumors located in critical areas . This technique has a high cure rate and allows maximum preservation of tissues. In this study, we aimed to assess the effectiveness of Mohs micrographic surgery and reconstruction methods. Method: Data from 50 patients who underwent Mohs micrographic surgery to excise skin tumors and reconstruct lost tissue were collected retrospectively. All patients were operated on between January 2005 and December 2013 at the Plastic Surgery Clinic of the Felício Rocho Hospital (Belo Horizonte, MG, Brazil). The patients' age, sex, tumor location, previous treatment, histological type, number of segments analyzed by micrographic surgery, reconstruction method used, and preservation were studied. Results: Thirtyone patients (62%) were women and 19 (38%) were men. The mean age was 63.8 years. All lesions were facial, with 66% of cases affecting the nasal area. Pre-surgery, there were 48 cases (96%) of basal cell carcinoma and 2 cases (4%) of microcystic adnexal carcinoma. Local flaps were the most used reconstruction method. The patients were followed-up for a mean of 48.4 months. We did not observe any cases of tumor recurrence. Conclusion: Mohs micrographic surgery was shown to be effective in the treatment of 50 skin neoplasms. We recommend that surgical defects should be repaired by the plastic surgeon.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , History, 21st Century , Skin Neoplasms , Wounds and Injuries , Carcinoma, Basal Cell , Medical Records , Efficacy , Data Interpretation, Statistical , Mohs Surgery , Plastic Surgery Procedures , Evaluation Study , Dichloroacetic Acid , Head and Neck Neoplasms , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Wounds and Injuries/surgery , Wounds and Injuries/complications , Carcinoma, Basal Cell/surgery , Carcinoma, Basal Cell/pathology , Medical Records/standards , Efficacy/methods , Mohs Surgery/adverse effects , Mohs Surgery/methods , Plastic Surgery Procedures/methods , Dichloroacetic Acid/adverse effects , Dichloroacetic Acid/therapeutic use , Dichloroacetic Acid/pharmacology , Head and Neck Neoplasms/surgery , Head and Neck Neoplasms/pathologyABSTRACT
Acidosis is a major contributing factor towards spread of the ischaemic focus in the brain. Drugs that increase pyruvate dehydrogenase activity could decrease the formation of lactic acidosis. The sodium salt of dichloracetic acid (DCA) has been found to be effective in reducing lactate. This study was undertaken to study the efficacy of DCA in reducing infarct size in experimental focal ischaemia in monkeys. Macaca radiata monkeys in the treatment group were given 35 mg per kilogram of dichloracetate intravenously immediately before occluding and interrupting the middle cerebral artery, and the control group was given saline as placebo under similar conditions. Mean infarct size expressed as a percentage of the size of the hemisphere in all the three brain slices was 35.38 in the control group as against l2.06 in the treated group (p=0. 0008).