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1.
Cancers (Basel) ; 15(19)2023 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-37835437

RESUMO

Osteosarcoma (OS) is the most common primary malignancy of the bone, highly aggressive and metastasizing, and it mainly affects children and adolescents. The current standard of care for OS is a combination of surgery and chemotherapy. However, these treatment options are not always successful, especially in cases of metastatic or recurrent osteosarcomas. For this reason, research into new therapeutic strategies is currently underway, and immunotherapies have received considerable attention. Mifamurtide stands out among the most studied immunostimulant drugs; nevertheless, there are very conflicting opinions on its therapeutic efficacy. Here, we aimed to investigate mifamurtide efficacy through in vitro and in vivo experiments. Our results led us to identify a new possible target useful to improve mifamurtide effectiveness on metastatic OS: the cytokine interleukin-10 (IL-10). We provide experimental evidence that the synergic use of an anti-IL-10 antibody in combination with mifamurtide causes a significantly increased mortality rate in highest-grade OS cells and lower metastasis in an in vivo model compared with mifamurtide alone. Overall, our data suggest that mifamurtide in combination with an anti-IL-10 antibody could be proposed as a new treatment protocol to be studied to improve the outcomes of OS patients.

2.
Front Pharmacol ; 12: 697912, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646131

RESUMO

The mechanisms involved in the development and maintenance of cancer pain remain largely unidentified. Recently, it has been reported that ß-adrenergic receptors (ß-ARs), mainly ß2-and ß3-ARs, contribute to tumor proliferation and progression and may favor cancer-associated pain and neuroinflammation. However, the mechanism underlying ß-ARs in cancer pain is still unknown. Here, we investigated the role of ß1-, ß2-and ß3-ARs in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. Results showed a rapid tumor growth in the soft tissue associated with the development of mechanical allodynia in the hind paw ipsilateral to the injected site. In addition to reduce tumor growth, both propranolol and SR59230A, ß1-/ß2-and ß3-AR antagonists, respectively, attenuated mechanical allodynia, the number of macrophages and an oxidative stress by-product accumulated in the ipsilateral tibial nerve. The selective ß1-AR antagonist atenolol was able to slightly reduce the tumor growth but showed no effect in reducing the development of mechanical allodynia. Results suggest that the development of the mechanical allodynia in K7M2 osteosarcoma-bearing mice is mediated by oxidative stress associated with the recruitment of neural macrophages, and that antagonism of ß2-and ß3-ARs contribute not solely to the reduction of tumor growth, but also in cancer pain. Thus, the targeting of the ß2-and ß3-ARs signaling may be a promising therapeutic strategy against both tumor progression and the development of cancer-evoke pain in osteosarcoma.

3.
Biochim Biophys Acta Proteins Proteom ; 1867(11): 140254, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31344531

RESUMO

The neurodegenerative disease Friedreich ataxia results from a deficiency of frataxin, a mitochondrial protein. Most patients have a GAA expansion in the first intron of both alleles of frataxin gene, whereas a minority of them are heterozygous for the expansion and contain a mutation in the other allele. Frataxin has been claimed to participate in iron homeostasis and biosynthesis of FeS clusters, however its role in both pathways is not unequivocally defined. In this work we combined different advanced spectroscopic analyses to explore the iron-binding properties of human frataxin, as isolated and at the FeS clusters assembly machinery. For the first time we used EPR spectroscopy to address this key issue providing clear evidence of the formation of a complex with a low symmetry coordination of the metal ion. By 2D NMR, we confirmed that iron can be bound in both oxidation states, a controversial issue, and, in addition, we were able to point out a transient interaction of frataxin with a N-terminal 6his-tagged variant of ISCU, the scaffold protein of the FeS clusters assembly machinery. To obtain insights on structure/function relationships relevant to understand the disease molecular mechanism(s), we extended our studies to four clinical frataxin mutants. All variants showed a moderate to strong impairment in their ability to activate the FeS cluster assembly machinery in vitro, while keeping the same iron-binding features of the wild type protein. This supports the multifunctional nature of frataxin and the complex biochemical consequences of its mutations.


Assuntos
Ataxia de Friedreich , Proteínas de Ligação ao Ferro/química , Ferro/química , Mutação , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Ferro/metabolismo , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Domínios Proteicos , Frataxina
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