Progestin and vitamin D synergistically inhibit fallopian tube carcinogenesis.

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.