Combining cashew gum with cyclophosphamide in murine melanoma model: A strategy for the reduction of side effects.

The understanding of cancer immunity and antitumor factors generated by natural polysaccharides is not yet fully comprehended. Polysaccharides, like cashew gum (CG), can exhibit immunomodulatory action and may assist in the antitumor process and side effects relieve. This study aimed to determine the antitumor effect of CG alone or in combination with cyclophosphamide (CTX), and its interactions with immune cells, in a murine melanoma model, using the B16-F10 cell line. Tumor growth inhibition, hematological, histopathological, ELISA, flow cytometry, immunofluorescence, and qRT-PCR analyses were performed to elucidate the antitumor potential, involvement of immune cells, and potential toxic effects. CG showed significant tumor growth inhibition, reaching up to 42.9 % alone and 51.4 % in combination with CTX, with mild toxicity to organs. CG enhanced leukocyte count, even in the presence of CTX. Furthermore, CG influenced the activation of tumor-associated macrophages (TAM), characterized by an increase in Il4, as well as a reduction in Ifng, Il1b, Tgfb, and Il6 gene expression. Nevertheless, these effects did not compromise the antitumor activity of CG. In summary, the combination of CG with CTX is a promising approach for leukopenia, one of the most important side effects of cancer treatment and deserves further investigation.

Biopolymer production by halotolerant bacteria isolated from Caatinga biome.

Saline environments are extreme habitats with a high diversity of microorganisms source of a myriad of biomolecules. These microorganisms are assigned as extremophiles recognized to be producers of new natural compounds, which can be synthesized by helping to survive under harshness and extreme conditions. In Brazil, in the saline and semi-arid region of Areia Branca (Caatinga biome), halotolerant bacteria (able to growth at high NaCl concentrations) were isolated from rhizosphere of native plants Blutaparon portulacoides and Spergularia sp. and their biopolymer production was studied. A total of 25 bacterial isolates were identified at genus level based on 16S rRNA gene sequence analysis. Isolates were mainly Gram-positive bacteria from Bacillaceae, Staphylococcaceae, Microbacteriaceae, and Bacillales XII incertae sedis families, affiliates to Bacillus, Staphylococcus, Curtobacterium, and Exiguobacterium genera, respectively. One of the Gram-negative isolates was identified as member of the Pseudomonadaceae family, genus Pseudomonas. All the identified strains were halotolerant bacteria with optimum growth at 0.6-2.0 M salt concentrations. Assays for biopolymer production showed that the halotolerant strains are a rich source of compounds as polyhydroxyalkanoates (PHA), biodegradable biopolymer, such as poly(3-hydroxybutyrate) (PHB) produced from low-cost substrates, and exopolysaccharides (EPS), such as hyaluronic acid (HA), metabolite of great interest to the cosmetic and pharmaceutical industry. Also, eight bacterial EPS extracts showed immunostimulatory activity, promising results that can be used in biomedical applications. Overall, our findings demonstrate that these biomolecules can be produced in culture medium with 0.6-2.0 M NaCl concentrations, relevant feature to avoid costly production processes. This is the first report of biopolymer-producing bacteria from a saline region of Caatinga biome that showed important biological activities.

SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4.

PURPOSE: Anticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed. METHODS: SN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA). Topotecan was used as a positive anti-inflammatory control. RESULTS: Non-cytotoxic concentrations of SN-38 attenuated LPS (a TLR4 agonist)-driven cell activation without affecting peptidoglycan (a TLR2 agonist)-activating response. Similarly, topotecan also prevented LPS-induced inflammation. Conversely, increasing concentrations of LPS reversed the SN-38 inhibitory effect. In addition, SN-38 abrogated LPS-dependent neutrophil migration and reduced TNF-α, IL-6, and keratinocyte chemoattractant levels in the air-pouch model, but failed to inhibit zymosan (a TLR2 agonist)-induced cell migration. A two-step molecular docking analysis indicated two potential binding sites for the SN-38 in the MD-2/TLR4 complex, the hydrophobic MD-2 pocket (binding energy of - 8.1 kcal/mol) and the rim of the same molecule (- 6.9 kcal/mol). The topotecan also bound to the MD-2 pocket. In addition, not only the lactone forms, but also the carboxylate conformations of both Top I inhibitors interacted with the MD-2 molecule. Furthermore, the TSA suggested the interaction of SN-38 with MD-2. CONCLUSIONS: Therefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors.