Search

High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.

Context: Tanshinone IIA (Tan IIA) is a constituent of Danshen Salvia miltiorrhiza Bunge (Lamiaceae); however, its antifatigue activity remains unclear. Objective: To study the antifatigue properties of Tan IIA and its underlying mechanisms. Materials and methods: In program I, three mouse groups were separately subjected to three gavages with 0, 1 and 6 mg/kg Tan IIA and forced swimming test (FST) weekly for 8 weeks; in program II, one gavage with 0, 2 and 10 mg/kg Tan IIA was administered plus FST weekly for 4 weeks. Serum glucose, lactate, superoxide dismutase (SOD), malondialdehyde (MDA) and blood urea nitrogen (BUN) were determined after final FST. Results: Tan IIA significantly prolonged swimming durations in program I but not in program II. Swimming times were 3208 ± 1054 and 2443 ± 1054 s for the 1 and 6 mg/kg treatments and 856 ± 292 s for the vehicle control. The two doses significantly reduced serum glucose levels (40.3 ± 8.5 and 60.0 1 ± 11.8 mg/kg) and lactate levels (61.3 ± 27.5 and 68.8 ± 8.5 mg/kg) in treated mice compared with those in control mice (137.5 ± 38.6 mg/kg and 122.7 ± 18.2 mg/kg, respectively). However, no significant differences were observed regarding SOD, MDA or BUN levels. Discussion and conclusions: Tan IIA has antifatigue activity and is associated with reductions in serum glucose and lactate levels. Further studies should assess muscle hypertrophy and efficient aerobic glycolysis caused by Tan IIA. Tan IIA has potential as a pharmacological agent for fatigue resistance.

Tanshinone IIA (Tan IIA) and sinapic acid (SA) are 2 components separately isolated from 2 Asian medicinal plants, Hydnophytum formicarum Jack and Salvia miltiorrhiza Bunge. The antitumor activities of them were worth exploring, therefore, we examined their antitumor activities in A549, HCT116, HeLa, and Colo320 cancer cell lines by means of WST-1 assay. The results show that Tan IIA exerted far higher (IC50 from 1.0±0.0 to 166.3 ±24.0 µg/mL) antiproliferative activities than SA (IC50 from 2236.3 ± 484.1 to >10 000.0 µg/mL). Of the 4 cell lines, A549 cells were the most sensitive to Tan IIA; thus, we used Western blotting to explore the cytotoxic mechanisms of Tan IIA in A549 cells and found that they rely on simultaneous induction of apoptosis and necroptosis in the cells. Apoptosis was hallmarked by the induction of cleaved caspase-3 by Tan IIA and necroptosis by the necroptotic marker proteins cyclophilin A and high mobility group box 1 (HMGB1), as well as increased lactate dehydrogenase (LDH) activities. The necroptotic effect was confirmed by the necroptosis inhibitor necrostatin-1 (Nec-1), which eliminated these effects and restored cell survival rates. The levels of cyclophilin A decreased in response to the pan-caspase inhibitor z-VAD-fmk, and those of cleaved caspase-3 decreased in response to Nec-1. Conclusively, Tan IIA has the potential to prevent lung cancer and the mechanism seems to be apoptosis and necroptosis, of which the relationship is mutually interdependent. This is the first report of Tan IIA eliciting necroptosis in A549 cells. Tan IIA may be used for necroptosis-based cancer therapy, especially to overcome apoptosis resistance. [ABSTRACT FROM AUTHOR]