Gynecologic oncology · 2026
Progestin and vitamin D synergistically inhibit fallopian tube carcinogenesis.
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Nelson Omar L, Rosales Rebecca, Turbov Jane, Thaete Larry G, Berlin Dillon, Balamayooran Gayathriy, Cline J Mark, Pike J Wesley, Conrads Kelly A, Conrads Thomas P, Maxwell G Larry, Rodriguez Gustavo C
Аннотация
OBJECTIVE: We previously showed that progestins and vitamin D synergistically inhibit ovarian cancer cell viability in vitro, and independently inhibit fallopian tube (FT) carcinogenesis in vivo by clearing p53-altered cells via apoptosis. This study sought to investigate whether vitamin D enhances progestin-mediated inhibition of FT carcinogenesis in the mogp-TAg mouse model and examine the underlying cellular mechanisms.
METHODS: Female mogp-TAg mice (5-week-old) were assigned to four treatment groups: progestin-Depo-medroxyprogesterone acetate (DMPA), vitamin D (cholecalciferol, Chole), DMPA/Chole (Combo), or vehicle (DMPA solvent) for 3, 5 or 7 weeks. FT tissues and blood were collected for analysis. Human primary and p53-altered fallopian tube epithelial (FTE) cells were used to examine the cellular mechanisms involved in inhibition of FT carcinogenesis.
RESULTS: At doses of progestin that modestly inhibited FT carcinogenesis in vivo, co-treatment with Chole synergistically reduced p53 signatures [Chou-Talalay Combination Index (CI); CI = 0.525], serous tubal intraepithelial carcinoma (CI = 0.603), and enhanced reduction in FT carcinoma incidence. In vitro, Combo treatment synergistically inhibited proliferation (CI = 0.491-0.858) and induced apoptosis and autophagy in p53-altered FTE cell lines, but not in normal FTE cells. Combo treatment of primary and p53-altered FTE cells led to significant reduction in the vitamin D inactivating enzyme CYP24A1. The induction of apoptosis was associated with CYP24A1 inhibition in p53-altered FTE cells in the combination treatment.
CONCLUSIONS: Both progestin and vitamin D individually inhibit FT carcinogenesis, but their combination was more potent than each agent alone. These findings support the potential of the combination of progestin and vitamin D as a chemopreventive strategy for fallopian tube/ovarian cancer.
METHODS: Female mogp-TAg mice (5-week-old) were assigned to four treatment groups: progestin-Depo-medroxyprogesterone acetate (DMPA), vitamin D (cholecalciferol, Chole), DMPA/Chole (Combo), or vehicle (DMPA solvent) for 3, 5 or 7 weeks. FT tissues and blood were collected for analysis. Human primary and p53-altered fallopian tube epithelial (FTE) cells were used to examine the cellular mechanisms involved in inhibition of FT carcinogenesis.
RESULTS: At doses of progestin that modestly inhibited FT carcinogenesis in vivo, co-treatment with Chole synergistically reduced p53 signatures [Chou-Talalay Combination Index (CI); CI = 0.525], serous tubal intraepithelial carcinoma (CI = 0.603), and enhanced reduction in FT carcinoma incidence. In vitro, Combo treatment synergistically inhibited proliferation (CI = 0.491-0.858) and induced apoptosis and autophagy in p53-altered FTE cell lines, but not in normal FTE cells. Combo treatment of primary and p53-altered FTE cells led to significant reduction in the vitamin D inactivating enzyme CYP24A1. The induction of apoptosis was associated with CYP24A1 inhibition in p53-altered FTE cells in the combination treatment.
CONCLUSIONS: Both progestin and vitamin D individually inhibit FT carcinogenesis, but their combination was more potent than each agent alone. These findings support the potential of the combination of progestin and vitamin D as a chemopreventive strategy for fallopian tube/ovarian cancer.