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Purpose: Breast cancer is the most common female malignancy and melanoma is the most lethal type of skin cancer. Traditional therapy for cancer treatment is far from satisfactory due to drug resistance and side effects, thus a search for new medicines is being emphasized. Palladium(II) complexes have been reported as anticancer potential agents. In this work, the anticancer activities and cell death induction of a new series of square-planar Pd(II) complexes were evaluated against MCF-7 and MDA-MB-435 cancer cells. Methods: MCF-7 (breast carcinoma) and MDA-MB-435 (melanoma) cells were cultivated, and treated with ligand and Pd(II) complexes. Cell growth, migration and adhesion inhibition, morphological alterations, cell death induction and, DNA interaction upon treatment were studied. Results: Pd(II) complexes exhibited both short and long-term antiproliferative effects on both cell lines, reducing by 80% cell growth in the SRB assay and abolishing longterm proliferation, estimated by the clonogenic assay. Complexes reduced significantly (P<0.05) cell migration and adhesion when compared to the control group. Complexes induced morphological alterations in cell lines and significant (P<0.05) cellular shrinkage. Cell death was induced and the complexes were able to interact with DNA, inducing cleavage of double-stranded DNA, which may account for the complexes cytotoxic effects, observed against both MCF-7 and MDA-MB-435 cells. Conclusion: Overall, the complexes exhibited cytotoxic activities and induced cell death. These observations emphasize an anticancer role with a potential therapeutic value for Pd(II) complexes to improve the outcome of patients with breast cancer and melanoma.

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BACKGROUND/AIM: Melanoma represents a big challenge for clinical treatment. Besides being the most aggressive and the deadliest form of skin cancer, it is often refractory to commonly used anticancer drugs. Hence, developing new anti-cancer agents is crucial to improve refractory melanoma treatment. Studies using palladium(II) complexes have reported antitumor effects on cancer cells. In this study, we aimed to determine the cytotoxic effect of three novel synthesized Pd(II) complexes with Schiff bases derived from 4-aminoacetophenone on the MDA-MB-435 melanoma cell line. MATERIALS AND METHODS: Cells were treated with ligand and Pd(II) complexes. Cell viability, morphology and death induction upon treatment were examined. RESULTS: Novel synthesized Pd(II) complexes led to decreased viability of cells. They also induced morphological alterations and cell death, mainly in the C3 complex. CONCLUSION: The novel synthesized complexes have a significant cytotoxic effect on cell line MDA-MB-435, especially C3 and can be considered as an antitumor agent for further studies.

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A anemia falciforme é a doença monogênica de maior ocorrência mundial e é causada pela presença de hemoglobina S (HbS), uma variante estrutural decorrente da substituição de um aminoácido na cadeia ß globina. Essa mutação altera as propriedades bioquímicas e fisiológicas da hemoglobina, que tem a tendência de formar agregados fibrilares, no estado desoxigenado, o que produz alterações morfológicas (falcização) e funcionais da hemácia. Assim, todas as manifestações clínicas observadas na doença decorrem da presença da HbS e têm início com a hemólise e a vaso-oclusão, desencadeando os demais eventos da doença, que podem afetar os órgãos e sistemas orgânicos. O tratamento baseia-se no controle dos sintomas. O único medicamento aprovado que altera o curso da doença é o antineoplásico hidroxiureia e, apesar de seu sucesso clínico, não é curativo e pode desencadear muitos efeitos adversos. O único tratamento curativo é o transplante de células tronco hematopoéticas. A terapia gênica vem sendo estudada há mais de 30 anos e alguns estudos clínicos estão sendo realizados. Novas abordagens moleculares como a edição do genoma, uso de RNA terapêutico e manipulação genética para indução da síntese de hemoglobina fetal emergem como possibilidades para a cura da doença. (AU)

Sickle cell anemia is the most common monogenic disease worldwide and it is caused by the presence of sickle hemoglobin (HbS), structural variant hemoglobin with one amino acid substitution in the ß globin chain. This mutation changes the biochemical and physiological properties of hemoglobin, which has the tendency, in the de-oxygenated state, to form fibrous aggregates, which produces morphological (sickling) and functional changes in red blood cells. Thus, all the observed disease clinical manifestations arise from the presence of HbS and begin with hemolysis of the red blood cell and vaso-occlusion, triggering other disease events, which can affect the body organs and systems as a whole. Nowadays, treatment is based mainly in symptoms control. The only drug approved that changes the course of the disease is the antineoplastic Hydroxyurea and, despite its clinical success, it is not curative and can trigger many adverse effects. The only curative treatment is the hematopoietic stem cells transplantation. Gene therapy has been studied for more than 30 years and some clinical studies are being in course. New molecular approaches as the genome editing, therapeutic RNA and genetic manipulation to stimulate fetal hemoglobin synthesis emerge as possible curative options for the disease. (AU)

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We evaluated the chemical composition, antioxidant activity, and antitumor potential of a fraction that was isolated from Stryphnodendron adstringens (barbatimão) leaf aqueous extract. Fraction is composed by gallic acid, procyanidin dimer B1, and (-)-epicatechin-3-O-gallate and it exhibits antioxidant and cytotoxic activities. Fraction was cytotoxic against two human breast cancer cell lines, ER (+) and MCF-7 and the triple-negative, MDA-MB-435. The sulforhodamine B assay showed that, as compared to normal control cells, the fraction significantly (P < 0.05) decreased cancer cell viability. The morphological alterations noted in the treated cancer cells were cell rounding-up, shrinkage, and nuclear condensation reduction of cell diameter and length. Treatment with fraction increased cancer cell expression of Bax, caspase-9, active caspase-3, caspase-8, LC-3, and beclin-1 and decreased Bcl-2, caspase-3, and pro-caspase-8 expression. Altogether, fraction is cytotoxic to both breast cancer cell lines, induces cell death, and its mechanism of action seems to include the induction of apoptosis. Our data support a positive role of the fraction as a chemopreventive agent for antineoplastic drug development.

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The antitumorigenic potential of two palladium(II) complexes, [Pd(ca(2)-o-phen)Cl(2)] - C1 and [Pd(dmba)(dppp)Cl] - C2, was evaluated, using MDA-MB-435 cells, a human breast adenocarcinoma cell-line that does not express the estrogen receptor α (ER-). Growth inhibition and induced alterations in cell-morphology were analyzed. The sulforhodamine B test showed that, compared to control cells, both C1 and C2 significantly inhibited (p < 0.5) cell growth. The maximum effect with both was achieved with 1 µM complexes, after 24 h of treatment. No further cell-growth inhibition was achieved by increasing concentration or incubation time. Cell morphology was analyzed after staining with hematoxylin-eosin (HE). The morphological changes noted in the treated cells were cell rounding-up, shrinkage, nuclear condensation and reduction of cell length (p < 0.05), thereby indicating that both C1 and C2 are cytotoxic to breast adenocarcinoma cells. All together, there was every indication that, by decreasing cell growth and inducing morphological changes, the tested complexes are cytotoxic, hence their potentiality as promising candidates for antineoplastic drug development.

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The antitumorigenic potential of two palladium(II) complexes, [Pd(ca2-o-phen)Cl2 ] - C1 and [Pd(dmba)(dppp)Cl] - C2, was evaluated, using MDA-MB-435 cells, a human breast adenocarcinoma cell-line that does not express the estrogen receptor α (ER-). Growth inhibition and induced alterations in cell-morphology were analyzed. The sulforhodamine B test showed that, compared to control cells, both C1 and C2 significantly inhibited (p < 0.5) cell growth. The maximum effect with both was achieved with 1 µM complexes, after 24 h of treatment. No further cell-growth inhibition was achieved by increasing concentration or incubation time. Cell morphology was analyzed after staining with hematoxylin-eosin (HE). The morphological changes noted in the treated cells were cell rounding-up, shrinkage, nuclear condensation and reduction of cell length (p < 0.05), thereby indicating that both C1 and C2 are cytotoxic to breast adenocarcinoma cells. All together, there was every indication that, by decreasing cell growth and inducing morphological changes, the tested complexes are cytotoxic, hence their potentiality as promising candidates for antineoplastic drug development.

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Alternagin-C (ALT-C) is a disintegrin-like, Cys-rich protein isolated from Bothrops alternatus snake venom, which has been shown to induce in vivo angiogenesis. Therefore, this protein could be interesting as a new approach for tissue regeneration studies. Here the effects of ALT-C on fibroblasts and inflammatory cells, collagen type III and type I and TGF-α expression in a rat wounded skin model were studied. Thirty-five male Wistar rats (weight 270 ± 20 g) were divided into seven groups with five animals in each of the following groups: a control group which wounded animals received treatment with natrozol(®) gel only; ALT-C10, ALT-C60 and ALT-C100 groups of wounded animals that were treated with the same amount of gel containing 10, 60 and 100 ng of ALT-C, respectively. Animals were treated once a day with 20 µl of gel associated or not with ALT-C for 1, 3, 5 or 7 days. ALT-C treatment increased the fibroblast density, collagen deposition and accelerated the inflammatory process, mostly in the ALT-C60 group. These results indicate that ALT-C improves wound repair process in rat skin. Thus, ALT-C could be a candidate to the development of a novel therapeutic strategy for wounded skin repair.

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In this work, we show that alternagin-C (ALT-C) and ALT-C PEP, a peptide derived from its sequence, were able to induce angiogenesis in wounded rat skin. A spherical cutaneous excision was made in the back of each animal and treated with three different concentrations of ALT-C or ALT-C PEP. After that, the skin was removed and analyzed to verify the presence of new vessels and the expression of growth factors. ALT-C and ALT-C PEP induced the formation of new vessels and modulated the expression of growth factors, mainly VEGF and FGF1. The expression of VEGF increased and it could be detected up to 7 days after injury. FGF1 also significantly increased, but at a lesser extent than VEGF. In conclusion, the present study shows for the first time the stimulation of angiogenesis in an injured tissue by a disintegrin-like protein and that ALT-C may exert this effect by modulating the expression of growth factors.

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PURPOSE: To investigate if ultrasonic therapy is effective in avoidance of incisional hernia (IH), once the ideal technique for repair of IH is still a non-solved problem, in despite of prostheses usage. METHODS: IH was created by linea alba opening over 20 male Wistar rats, distributed in two groups: one group received the ultrasound, over the wound, during 14 days (5 animals) and the other for 28 days (5 animals), each one with the same number of animals as controls. The ultrasound was applied using a small probe, 1:5 pulse mode, 3.0 MHz frequency and 0.5W/cm2 intensity, for 5 minutes daily, from the first postoperative day. The width of the linea alba scar or the hernia ring was measured at the end of every period. The IH was defined when these openings were over 2mm wide. Some specimens from hernia sac or linea alba scar were obtained for vessels, fibroblasts, and colagen fibers density. Standard deviation and medians were obtained by variation analysis and Tukey-Kramer multi-comparison test. RESULTS: The ultrasound group showed a linea alba scar in 60%. The other 40% presented the hernia ring smaller than the non treated group (p < 0.0001). The ultrasound increased density of blood vessels (p = 0.0031), fibroblasts (p < 0.0001), and collagen fibers (p = 0.0015). There was no difference between the two treated groups. CONCLUSION: The ultrasound avoided the IH to appear or reduced its width. Fourteen days of treatment were sufficient for this purpose.

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OBJETIVO: Investigar se o ultra-som é capaz de evitar o aparecimento da hérnia incisional (HI), uma vez que o seu tratamento ainda é um problema não resolvido. MÉTODO: Induziu-se a HI, por secção da linha alba, em 20 ratos Wistar, distribuídos em dois grupos: um recebeu a aplicação do ultra-som, na área operada, por 14 dias e o outro por 28 dias, cada qual com seu subgrupo controle (não tratado). Utilizou-se aparelho com cabeçote reduzido, modo pulsado (1:5), freqüência de 3,0MHz e intensidade de 0,5W/cm², durante 5min/dia, iniciando-se as aplicações no primeiro dia pós-operatório. Ao final, mediu-se o diâmetro transverso do anel herniário ou da largura da cicatriz na linha alba, definindo-se a HI quando esses valores ultrapassassem 2mm. A densidade de vasos sangüíneos, de fibroblastos e de fibras colágenas, nessas estruturas, foi estudada à microscopia óptica. As médias e o erro padrão foram submetidos à análise de variância (ANOVA) e ao teste de comparação múltipla de Tukey-Kramer. RESULTADOS: Dos animais tratados com o ultra-som, 60 por cento não desenvolveram HI e, nos restantes, o anel herniário foi menor do que os não tratados (p<0,0001). A densidade de vasos sangüíneos (p=0,0031), de fibroblastos (p<0,0001) e de fibras colágenas (p=0,0015) também foi maior, em relação aos controles. Não houve diferença significante nesses parâmetros, comparando-se os dois períodos de tratamento. CONCLUSÃO: O ultra-som evitou o aparecimento da HI ou reduziu o seu tamanho, quando aplicado por 14 dias pós-operatórios, nas condições deste experimento.

BACKGROUND: To investigate if ultrasonic therapy is effective in avoidance of incisional hernia (IH), once the ideal technique for repair of IH is still a non-solved problem, in spite of prostheses usage. METHODS: IH was created by linea alba opening over 20 male Wistar rats, distributed in two groups: one group received ultrasound over the wound, during 14 days (5 animals) and the other for 28 days (5 animals), each one with the same number of animals as controls. The ultrasound was applied using a small probe, 1:5 pulse mode, 3.0MHz frequency and 0.5W/cm² intensity, for 5 minutes daily, from the first postoperative day. The width of the linea alba scar or the hernia ring was measured at the end of every period. The IH was defined when these openings were over 2mm wide. Some specimens from hernia sac or linea alba scar were obtained for the analysis of vessels, fibroblasts, and colagen fibers density. Standard deviation and medians were obtained by variation analysis and Tukey-Kramer multi-comparison test. RESULTS: The ultrasound group showed a linea alba scar in 60 percent. The other 40 percent presented the hernia ring smaller than the non treated group (p<0.0001). The ultrasound increased density of blood vessels (p=0,0031), fibroblasts (p<0,0001), and collagen fibers (p=0,0015). There was no difference between the two treated groups. CONCLUSION: The ultrasound avoided the IH to appear or reduced its width. Fourteen days of treatment were sufficient for this purpose.

RESUMO

OBJETIVO: Investigar se o ultra-som é capaz de evitar o aparecimento da hérnia incisional (HI), uma vez que o seu tratamento ainda é um problema não resolvido. MÉTODOS: Induziu-se a HI, por secção da linha alba, em 20 ratos Wistar, distribuídos em dois grupos: um recebeu a aplicação do ultra-som, na área operada, por 14 dias e o outro por 28 dias, cada qual com seu subgrupo controle (não tratado). Utilizou-se aparelho com cabeçote reduzido, modo pulsado (1:5), freqüência de 3,0MHz e intensidade de 0,5W/cm², durante 5min/dia, iniciando-se as aplicações no primeiro dia de pós-operatório. Ao final, mediu-se o diâmetro transverso do anel herniário ou da largura da cicatriz na linha alba, definindo-se a HI quando esses valores ultrapassassem 2mm. A densidade de vasos sangüíneos, de fibroblastos e de fibras colágenas, nessas estruturas, foi estudada à microscopia óptica. As médias e o erro padrão foram submetidos à análise de variância (ANOVA) e ao teste de comparação múltipla de Tukey-Kramer. RESULTADOS: Dos animais tratados com o ultra-som, 60 por cento não desenvolveram a HI e, nos restantes, o anel herniário foi menor do que os não tratados (p<0,0001). A densidade de vasos sangüíneos (p=0,0031), de fibroblastos (p<0,0001) e de fibras colágenas (p=0,0015) também foi maior, em relação aos controles. Não houve diferença significante nesses parâmetros, comparando-se os dois períodos de tratamento. CONCLUSAO: O ultra-som evitou o aparecimento da HI ou reduziu o seu tamanho, quando aplicado por 14 dias no pós-operatórios.

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OBJETIVO: Investigar se o ultra-som é capaz de evitar o aparecimento da hérnia incisional (HI), uma vez que o seu tratamento ainda é um problema não resolvido. MÉTODOS: Induziu-se a HI, por secção da linha alba, em 20 ratos Wistar, distribuídos em dois grupos: um recebeu a aplicação do ultra-som, na área operada, por 14 dias e o outro por 28 dias, cada qual com seu subgrupo controle (não tratado). Utilizou-se aparelho com cabeçote reduzido, modo pulsado (1:5), freqüência de 3,0MHz e intensidade de 0,5W/cm², durante 5min/dia, iniciando-se as aplicações no primeiro dia de pós-operatório. Ao final, mediu-se o diâmetro transverso do anel herniário ou da largura da cicatriz na linha alba, definindo-se a HI quando esses valores ultrapassassem 2mm. A densidade de vasos sangüíneos, de fibroblastos e de fibras colágenas, nessas estruturas, foi estudada à microscopia óptica. As médias e o erro padrão foram submetidos à análise de variância (ANOVA) e ao teste de comparação múltipla de Tukey-Kramer. RESULTADOS: Dos animais tratados com o ultra-som, 60 por cento não desenvolveram a HI e, nos restantes, o anel herniário foi menor do que os não tratados (p<0,0001). A densidade de vasos sangüíneos (p=0,0031), de fibroblastos (p<0,0001) e de fibras colágenas (p=0,0015) também foi maior, em relação aos controles. Não houve diferença significante nesses parâmetros, comparando-se os dois períodos de tratamento. CONCLUSAO: O ultra-som evitou o aparecimento da HI ou reduziu o seu tamanho, quando aplicado por 14 dias no pós-operatórios.

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OBJETIVO: Investigar se o ultra-som é capaz de evitar o aparecimento da hérnia incisional (HI), uma vez que o seu tratamento ainda é um problema não resolvido. MÉTODOS: Induziu-se a HI, por secção da linha alba, em 20 ratos Wistar, distribuídos em dois grupos: um recebeu a aplicação do ultra-som, na área operada, por 14 dias e o outro por 28 dias, cada qual com seu subgrupo controle (não tratado). Utilizou-se aparelho com cabeçote reduzido, modo pulsado (1:5), freqüência de 3,0MHz e intensidade de 0,5W/cm², durante 5min/dia, iniciando-se as aplicações no primeiro dia de pós-operatório. Ao final, mediu-se o diâmetro transverso do anel herniário ou da largura da cicatriz na linha alba, definindo-se a HI quando esses valores ultrapassassem 2mm. A densidade de vasos sangüíneos, de fibroblastos e de fibras colágenas, nessas estruturas, foi estudada à microscopia óptica. As médias e o erro padrão foram submetidos à análise de variância (ANOVA) e ao teste de comparação múltipla de Tukey-Kramer. RESULTADOS: Dos animais tratados com o ultra-som, 60 por cento não desenvolveram a HI e, nos restantes, o anel herniário foi menor do que os não tratados (p<0,0001). A densidade de vasos sangüíneos (p=0,0031), de fibroblastos (p<0,0001) e de fibras colágenas (p=0,0015) também foi maior, em relação aos controles. Não houve diferença significante nesses parâmetros, comparando-se os dois períodos de tratamento. CONCLUSAO: O ultra-som evitou o aparecimento da HI ou reduziu o seu tamanho, quando aplicado por 14 dias no pós-operatórios. (AU)

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