Danazol enhances Fas-mediated apoptosis in human endometrial epithelial cells within normal physiology

Abstract

Abstract. Local danazol therapy reduces the signs and symptoms of endometriosis without inhibition of regular ovulation and menstruation and without atrophic changes to the endometrium or vaginal wall. It has been suggested that danazol has possible non-cytotoxic direct actions on eutopic endometrial cells and endometriotic cells. We have investigated the direct effects of danazol on a human endometrial epithelial cell line, HHUA, which is believed to retain many normal intracellular signaling pathways. A thoroughly dissolved solution of danazol enhanced Fasmediated apoptosis in HHUA cells without inhibiting cell proliferation. Semi-quantitative flow cytometric analysis revealed that danazol did not enhance cell surface expression of Fas antigens. The enhancement of Fas-mediated apoptosis by endometrial cytokines such as EGF, IL-1ß and interferon-Á was not additively enhanced by danazol; nor did danazol enhance growth suppression by anticancer drugs such as paclitaxel, carboplatin and 5-fluorouracil. Moreover, danazol did not enhance the irradiation-induced cell growth suppression of radiation-sensitive human cervical squamous cancer ME180 cells. These results indicate that danazol may regulate endometrial epithelial cell proliferation and apoptosis within normal physiology.

Danazol regulates the functions of normal human endometrial stromal cell subpopulations by modifying endometrial cytokine networks

“…Recently, we found that danazol enhances Fas-mediated apoptotic signals within physiological variations (27). The present study has revealed that danazol regulates the functional cellular subpopulation ratios of ESCs by different mechanisms from M-CSF (30).…”

“…However, in vitro experiments using thoroughly dissolved danazol in 0.5% ethanol revealed that even high concentrations of danazol did not inhibit the proliferation rates of endometrial epithelial cells and ESCs (25). Moreover, we recently reported that danazol enhances Fas-mediated apoptosis within physiological variations (27). In the present study, we examined the effects of danazol on normal human ESCs.…”

“…Regarding endometrial epithelial cells, we recently demonstrated that thoroughly dissolved danazol enhances Fasmediated apoptotic signals but not anticancer drug-induced apoptotic signals in the human endometrial epithelial cell line HHUA (27). Endometrial epithelial cell growth and viability can be regulated in vivo by ESCs in paracrine manner.…”

Danazol induces apoptosis and cytotoxicity of leukemic cells alone and in combination with purine nucleoside analogs in chronic lymphocytic leukemia

“…However, literature data regarding diseases other than CLL show a similar mechanism of action of danazol. Tanaka et al [ 28 ] showed that danazol enhanced Fas-mediated apoptosis in human endometrial epithelial cells, indicating involvement of a receptor cascade. However, another study reported that expression of BCL-2 was decreased in adenomyotic endometrium treated with danazol, which indicated activation of a mitochondrial cascade [ 29 ].…”

Investigational Medical Therapies for Endometriosis: Current Data and Future Trends

“…32 The underlying mechanism is to be fully elucidated, but Fasmediated apoptosis and inhibition of aromatase gene transcription have been implicated. [33][34][35] The use of oral danazol has been limited by its androgenic side effects, which make compliance difficult and limit prolonged use. Recent interest has focused on alternative, more targeted routes of administration that would limit its systemic androgenic side effects.…”