Trabectedin impairs invasiveness and metastasis in adrenocortical carcinoma preclinical models
| Autor: | Andrea Abate, Mariangela Tamburello, Elisa Rossini, Ram Manohar Basnet, Giovanni Ribaudo, Alessandra Gianoncelli, Constanze Hantel, Deborah Cosentini, Marta Laganà, Salvatore Grisanti, Guido Alberto Massimo Tiberio, Maurizio Memo, Alfredo Berruti, Sandra Sigala |
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| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Cancer Research
Endocrinology Diabetes and Metabolism 10265 Clinic for Endocrinology and Diabetology 610 Medicine & health ACC cell cultures cell invasiveness metastasis zebrafish embryos Adrenal Cortex Neoplasms 1310 Endocrinology 2712 Endocrinology Diabetes and Metabolism Endocrinology Oncology Cell Line Tumor Adrenocortical Carcinoma Humans Matrix Metalloproteinase 2 2730 Oncology 1306 Cancer Research Trabectedin |
| Popis: | The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells’ invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients. |
| Databáze: | OpenAIRE |
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