ABSTRACT
The content of tumor-derived extracellular vesicles (EVs) can regulate the tumor microenvironment and functionally acts in favor of cancer aggressiveness. To better elucidate the role of EVs in the interplay between immune system and tumor microenvironment, the purpose of this study was to analyze the effect of head and neck squamous cells carcinoma (HNSCC)-derived EVs on the modulation of inflammasomes - mediators of pyroptosis and secretion of inflammatory factors by macrophages. Our results showed that macrophages treated with the Vesicular Secretome Fraction (VSF) isolated from patient-derived HNSCC presented a reduction in the secretion of mature IL-1ß and caspase-1 without affecting cell viability. An analysis of the protein content of HNSCC-derived VSF by antibody array revealed that some of the most expressed proteins share a correlation with Transforming Growth Factor-beta (TGF-ß) activity. Since TGF-ß is related to the inhibition of the NF-kB-related pathways, including those required for the priming phase of the inflammasomes, we sought to evalute the interference of the VSF in the induction of inflammasome components. In fact, HNSCC-derived VSF inhibited the induction of pro-IL-1ß and pro-caspase-1 proteins and NLRP3 gene expression during the priming phase of inflammasome activation. Thus, our findings contribute to a better understanding of how tumor-derived EVs modulate inflammatory response by demonstrating their role in inhibiting NLRP3 inflammasomes.
ABSTRACT
Purpose Among alkaloids, abundant secondary metabolites in plants, aporphines constitute a class of compounds with interesting biological activities, including anticancer effects. The present study evaluated the anticancer activities of 14 substances, including four aporphine derivatives acquired through the biomonitoring of (±)-apomorphine hydrochloride total synthesis from 2-phenethylamine and 3,4-dimethoxybenzaldehyde against head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic effects of compounds against a panel of HNSCC cell lines were determined by PrestoBlue cell viability assay, while the genotoxicity of substances was evaluated by micronucleus test. Cell death was detected by flow cytometry (Annexin V/7AAD) and western blot analysis was used to detect the presence of cleaved Caspase-3 molecules. Results The aporphine and isoquinoline derivatives APO, C1, and A5 significantly reduced HNSCC cell viability and promoted DNA damages in these cells. Further, by activating the Caspase-3 pathway, these substances were able to induce apoptosis. Conclusion Our results revealed that APO, C1, and A5 exhibit cytotoxic effects in HNSCC cells. The mechanisms of action appear to be partly via the generation of DNA damages and apoptosis induction through Caspase-3 pathway activation. This study provides preclinical data that suggest a potential therapeutic role for APO, C1, and A5 against head and neck cancer cells.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Aporphines/chemistry , Head and Neck Neoplasms/pathology , Squamous Cell Carcinoma of Head and Neck/pathology , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis , Aporphines/pharmacology , Caspase 3/metabolism , Cell Proliferation , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/metabolism , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/metabolism , Tumor Cells, CulturedABSTRACT
Multiple myeloma (MM) is an incurable disease; a better understanding of the molecular aspects of this hematological malignancy could contribute to the development of new treatment strategies and help to improve the survival rates of patients with MM. Previously, the methylation status of the deleted in colorectal cancer (DCC) gene was correlated with the survival rate of patients with MM, thus the main goal of this study was to understand DCC contribution to MM tumorigenesis, and to assess the impact of DCC inhibition in the MM response to treatment with bortezomib. Our results demonstrated that hypermethylation of the DCC promoter inhibits gene expression, and DCC silencing is significantly correlated with a reduction in cell viability and an increase in cell death induced by bortezomib. In conclusion, our results suggested that hypermethylation is an important mechanism of DCC expression regulation in MM and that the absence of DCC contributes to the enhanced sensitivity to treatment with bortezomib.