Effect of progesterone and first evidence about allopregnanolone action on the progression of epithelial human ovarian cancer cell lines

ARTÍCULO PUBLICADO EN REVISTA EXTERNA. Ovarian carcinoma is one of the most common cause of death by gynecologic cancer. Several epidemiological and in vitro studies have shown controversial data about progesterone effects in ovarian cancer. Progesterone can be converted in its active metabolite, allopregnanolone, its effects in ovarian cancer are still unknown. Previously, we demonstrated that allopregnanolone modifies ovarian morphophysiology, being able to alter critical process of tumor development such as proliferation, apoptosis and angiogenesis. Taking into account these antecedents, we investigated the effect of progesterone and allopregnanolone on proliferation, apoptosis, clonogenic capacity and migration on two epithelial human ovarian cancer cell lines, IGROV-1 and SKOV-3. To this end, IGROV-1 and SKOV-3 cells were exposed to a range of progesterone and allopregnanolone concentrations (10-11 to 10-5 M) for 72 h. Proliferation was analyzed by MTT and Ki67 expression. Apoptosis was measured by immunocytochemistry of cleaved caspase 3. Clonogenic capacity was evaluated by counting colonies. Migration was analyzed by wound assay. We found that allopregnanolone increased proliferation and Ki67 expression respect to control on IGROV-1 cells, while expression of cleaved caspase 3 did not change in any cell line studied. IGROV-1 clonogenic capacity was also increased by allopregnanolone treatment. Both steroids, progesterone and allopregnanolone, increased IGROV-1 migration in a concentration dependent manner. None of the steroids tested modified SKOV-3 biological behavior analized. This is the first evidence that allopregnanolone, a progesterone metabolite, affects critical events in tumor development of human epithelial ovarian cancer. These results could have an impact in the future in clinic diagnosis, prognosis and treatment of ovarian cancer patients. The regulation of progesterone and allopregnanolone steroideogenesis and their molecular mechanisms might be considered as potential therapeutic tool in ovarian cancer. Sitio de la revista: https://www.sciencedirect.com/science/article/pii/S0960076019301013?via%3Dihu

Dehydroleucodine inhibits tumor growth in a preclinical melanoma model by inducing cell cycle arrest, senescence and apoptosis

Malignant melanoma represents the fastest growing public health risk of all cancer types worldwide. Several strategies and anti-cancer drugs have been used in an effort to improve treatments, but the development of resistance to anti-neoplastic drugs remains the major cause of chemotherapy failure in melanomas. Previously, we showed that the sesquiterpene lactone, dehydroleucodine (DhL), promotes the accumulation of DNA damage markers, such as H2AX and 53BP1, in human tumor cells. Also DhL was shown to trigger either cell senescence or apoptosis in a concentration-dependent manner in HeLa and MCF7 cells. Here, we evaluated the effects of DhL on B16F0 mouse melanoma cells in vitro and in a pre-clinical melanoma model. DhL inhibited the proliferation of B16F0 cells by inducing senescence or apoptosis in a concentration-dependent manner. Also, DhL reduced the expression of the cell cycle proteins cyclin D1 and B1 and the inhibitor of apoptosis protein, survivin. In melanomas generated by subcutaneous injection of B16F0 cells into C57/BL6 mice, the treatment with 20 mg DhL /Kg/day in preventive, simultaneous and therapeutic protocols reduced tumor volumes by 70%, 60% and 50%, respectively. DhL treatments reduced the number of proliferating, while increasing the number of senescent and apoptotic tumor cells. To estimate the long-term effects of DhL, a mathematical model was applied to fit experimental data. Extrapolation beyond experimental time points revealed that DhL administration following preventive and therapeutic protocols is predicted to be more effective than simultaneous treatments with DhL in restricting tumor growth.Fil: Costantino, Valeria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Lobos Gonzalez, Lorena. Universidad de Chile; ChileFil: Ibañez, Jorge Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Fernandez, Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Valenzuela, Manuel A.. Universidad de Chile; ChileFil: Barbieri, Manuel A.. Florida International University; Estados UnidosFil: Semino, Silvana N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Jahn, Graciela Alma. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Quest, Andrew F.G.. Universidad de Chile; ChileFil: Lopez, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin