Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress

Skin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma

A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

<p>Abstract</p> <p>Background</p> <p>Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd₂[<it>S_(-)</it>C², N-dmpa]₂(μ-dppe)Cl₂} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies.</p> <p>Methods</p> <p>B16F10-Nex2 cells were treated <it>in vitro </it>with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated <it>in vitro </it>with C7a.</p> <p>Results</p> <p>Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages <it>in vitro</it>, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells.</p> <p>Conclusions</p> <p>The cyclopalladated C7a complex is an effective chemotherapeutic anticancer compound against primary and metastatic murine and human tumors, including cisplatin-resistant cells, inducing apoptotic cell death via the intrinsic pathway.</p

Migrantes, pós-colonialismo e fundamentalismo: enlaces entre Oriente e Ocidente e a questão do Islã

Neste artigo foi abordado o enlace entre Oriente e Ocidente nas questões sociais e geopolíticas do século XX e início do XXI. Realiza-se uma breve análise sobre o colonialismo europeu e a sua construção considerando o mundo árabe e islâmico, os fluxos migratórios para os países centrais e a origem do fundamentalismo no Ocidente. As questões atuais se desdobram a partir da construção do orientalismo, da dominação política e econômica que levou à formação de estereótipos e preconceitos com o árabe e o islã. O objetivo é apresentar elementos para uma reflexão a respeito da migração dos árabes e muçulmanos no contexto das guerras e conflitos do século XX e início deste século. Também visa esclarecer a origem dos estereótipos e reforçar a necessidade do conhecimento do outro para que o diálogo e a coexistência estejam no centro do debate.</p

Migrants, post-colonialism and fundamentalism: links between East and West and the issue of Islam

;En este artículo se abordó el enlace entre Oriente y Occidente en las cuestiones sociales y geopolíticas del siglo XX y principios del XXI. Se realizó un breve análisis acerca del colonialismo europeo y su construcción considerando el mundo árabe e islámico, los flujos migratorios para los países centrales y la origen del fundamentalismo en el Occidente. Las cuestiones actuales se desdoblan a partir de la construcción del orientalismo, de la dominación política y económica que llevó a la formación de estereotipos y prejuicios hacia el árabe y el islam. El objetivo es la presentación de elementos para la reflexión acerca de la migración de los árabes y musulmanes en el contexto de guerras y conflictos del siglo XX y principios de este siglo. También tiene por objetivo aclarar la origen de los estereotipos y reforzar la necesidad del conocimiento del otro para que el diálogo y la coexistencia estén en el centro del debate.;Neste artigo foi abordado o enlace entre Oriente e Ocidente nas questões sociais e geopolíticas do século XX e início do XXI. Realiza-se uma breve análise sobre o colonialismo europeu e a sua construção considerando o mundo árabe e islâmico, os fluxos migratórios para os países centrais e a origem do fundamentalismo no Ocidente. As questões atuais se desdobram a partir da construção do orientalismo, da dominação política e econômica que levou à formação de estereótipos e preconceitos com o árabe e o islã. O objetivo é apresentar elementos para uma reflexão a respeito da migração dos árabes e muçulmanos no contexto das guerras e conflitos do século XX e início deste século. Também visa esclarecer a origem dos estereótipos e reforçar a necessidade do conhecimento do outro para que o diálogo e a coexistência estejam no centro do debate.;Résumé;;Dans cet article, on fait une approche des questions telles que le lien entre l' Orient et l'Occident en ce qui concerne les problèmes sociaux et géopolitiques du XXe siècle et au début du XXIe siècle. Dans une brève analyse on présent de certaines questions fondamentales du colonialisme européen et sa construction en lien avec le monde arabe et islamique, la migration vers les pays de base et la montée du fondamentalisme dans l'Occident. Les conflits actuels ont été développés à partir de la construction de l'orientalisme, de la domination politique et économique qui a conduit à la formation des stéréotypes et des préjugés envers l'arabe et l'islam. La situation conflictuelle aujourd'hui est fondé sur les intérêts géopolitiques et économiques, beaucoup plus que les différences culturelles ou religieuses. L'article vise à clarifier certains des stéréotypes, en indiquant des liens possibles, et à renforcer la nécessité d'une connaissance de l'autre pour mettre le dialogue et la coexistence au centre du débat.;;In this article, the link between East and West in social and geopolitical issues of the twentieth and early twenty-first centuries was approached. A brief analysis of European colonialism and its construction considering the Arab and Islamic world, migration to the central countries and the rise of orientalism was conducted. Current issues unfold from the construction of orientalism, the political and economic domination that led to the formation of stereotypes and prejudices towards the Arab and Islam. The goal is to provide elements for a reflection on the migration of Arabs and Muslims in the context of wars and conflicts of the twentieth century and beginning of this century. It also aims to clarify the origin of stereotypes and reinforce the need for knowledge of the other so that dialogue and coexistence are at the center of the debate.

Impact of water and nitrogen depletion on the Peach orchard infestation by green peach aphid (Myzus persicae) and its relation with the useful fauna

This work aims to establish an ecologically integrated pest management strategy to assess the effect of water and nitrogen depletion on Myzus persicae infestation in the peach orchard. The results showed a significant effect of level of water and nitrogen supplies on the green peach aphid infestation in the orchard. Indeed, the fertigation regime T1 (100%) proved to be much more favorable to a prominent development of aphidian populations compared to 25% water and nitrogen restricted regime. Moreover, the infestation degree was lower in the regime T2 (~75%) than that observed in the regime T1. The evolution of wingless and winged green aphid populations was similar in both regimes. The effect of branch orientation on the aphids infestation was significant with those oriented to the North, West and South were more infested than those oriented to the East. Concerning the useful fauna, we noticed the same predators species for all the tested regimes. A negative effect on Stethorus sp and Chrysoperla carnea densities was appeared under water and nitrogen depletion

Autophagy as a Neuroprotective Mechanism Against 3-Nitropropionic Acid-Induced Murine Astrocyte Cell Death

Huntington's disease (HD) is a genetic neurodegenerative disorder that is characterized by severe striatal atrophy with extensive neuronal loss and gliosis. Although the molecular mechanism is not well understood, experimental studies use the irreversible mitochondrial inhibitor 3-nitropropionic acid (3-NP) to mimic the neuropathological features of HD. in this study, the role of autophagy as a neuroprotective mechanism against 3-NP-induced astrocyte cytotoxicity was evaluated. Autophagy is a catabolic process that is essential for the turnover of cytosolic proteins and organelles and is involved in the modulation of cell death and survival. We showed that 3-NP-induced apoptosis, which was accompanied by Bax and Beclin-1 upregulation, was dependent on acidic vesicular organelle (AVO) formation after a continuous exposure to 3-NP for 12 h. the upregulation of Bax and Beclin-1 as well as AVO formation were normalized 24 h after 3-NP exposure.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fed Univ São Paulo UNIFESP, Dept Pharmacol, BR-04044020 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Pharmacol, BR-04044020 São Paulo, BrazilWeb of Scienc

EVALUATION OF THE INTESTINAL-MUCOSA BARRIER BY A PHARMACOLOGICAL APPROACH

ESCOLA PAULISTA MED,DEPT PHARMACOL,BR-04023 SAO PAULO,BRAZILESCOLA PAULISTA MED,DEPT PATHOL,BR-04023 SAO PAULO,BRAZILESCOLA PAULISTA MED,DEPT PHARMACOL,BR-04023 SAO PAULO,BRAZILESCOLA PAULISTA MED,DEPT PATHOL,BR-04023 SAO PAULO,BRAZILWeb of Scienc