Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

• Published in: International journal of molecular sciences Vol. 24; no. 7; p. 6829
• Main Authors: Tamburello, Mariangela, Abate, Andrea, Rossini, Elisa, Basnet, Ram Manohar, Zizioli, Daniela, Cosentini, Deborah, Hantel, Constanze, Laganà, Marta, Tiberio, Guido Alberto Massimo, Grisanti, Salvatore, Memo, Maurizio, Berruti, Alfredo, Sigala, Sandra
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: ACC cell lines; Acetic acid; Adrenal Cortex Neoplasms - metabolism; adrenocortical carcinoma; Adrenocortical Carcinoma - pathology; Analysis; Animals; Apoptosis; Autophagy; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Chemotherapy; Cisplatin; Cytotoxicity; Doxorubicin; Embryos; Endometrial cancer; Etoposide; Flow cytometry; Gelatinase A; Health aspects; Humans; invasion; Malignancy; Matrix Metalloproteinase 2; Megestrol; Metastases; Metastasis; Neuroendocrine tumors; Progesterone; Progesterone - pharmacology; Progesterone - therapeutic use; Prognosis; Scientific equipment and supplies industry; Tumor cell lines; Xenografts; Xenotransplantation; Zebrafish; zebrafish model; United States; Germany; autophagy; ACC cell lines; invasion; metastasis; progesterone; migration; zebrafish model; adrenocortical carcinoma; apoptosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076829

Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.