RESUMEN
Small molecule drugs containing morpholine-based moieties have become crucial candidates in the tumor targeted therapy strategies, but the specific molecular mechanisms of these drugs causing tumor cell death require further investigation. The morpholine derivative N-(4-morpholinomethylene)ethanesulfonamide (MESA) was used to stimulate prostate and ovarian cancer cells and we focused on the ferroptosis effects, including the target molecule and signal pathways mediated by MESA. The results showed that MESA could induce ferroptosis to cause the proliferation inhibition and apoptosis effects of tumor cells according to the identification of ferroptosis inhibitor fer-1 and other cell death inhibitors. Further MESA could significantly increase the intracellular malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+ levels in tumor cells and mediate the dynamic changes of ferroptosis-relative molecules GPX4, nuclear factor erythroid2-related factor 2 (NRF2), ACSL4, SLC7A11 and P62-Kelch-like ECH-associated protein 1 (KEAP1)-NRF2-antioxidant response element (ARE) signal pathways. Further, NRF2 overexpression could reduce the tumor cell death and ROS levels exposure to MESA. Most importantly, it was confirmed that MESA could bind to NRF2 protein through molecular docking and thermal stability assays and NRF2 was a target molecule of MESA for inducing ferroptosis effects in tumor cells. Collectively, our findings indicated the ferroptosis effects of the morpholine derivative MESA in prostate and ovarian cancer cells and its function mechanism including targeted molecule and signal pathways, which would be helpful for developing MESA as a prospective small molecule drug for cancer therapy based on cell ferroptosis.
Asunto(s)
Ferroptosis , Neoplasias Ováricas , Masculino , Femenino , Humanos , Proteína 1 Asociada A ECH Tipo Kelch , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2 , Estudios Prospectivos , Especies Reactivas de Oxígeno , Morfolinas/farmacología , Neoplasias Ováricas/tratamiento farmacológicoRESUMEN
AIM: We investigated the influence of carbon dioxide (CO2) pneumoperitoneum on the growth hormone(GH)-insulin-like growth factor I (IGF-I) axis in mid- and late-pregnancy Sprague-Dawley rats. METHODS: A total of 48 mid-pregnancy rats were randomly assigned to one of three groups: anesthesia only (control group); 1-h CO2 pneumoperitoneum; or 2-h CO2 pneumoperitoneum. Blood samples were collected immediately after the procedure or in late pregnancy. Maternal concentration of serum GH and IGF-I was measured on enzyme-linked immunosorbent assay and compared between different groups. RESULTS: Under the same CO2 pneumoperitoneum pressure, serum GH and IGF-I concentration in the 2-h pneumoperitoneum group were significantly lower than those of the 1-h pneumoperitoneum group or the control group in both mid- and late pregnancy (P < 0.05), but there was no significant difference between the 1-h pneumoperitoneum group and the control group (P > 0.05). Serum GH and IGF-I concentrations were positively correlated in pregnant rats (R(2) = 0.3434, P < 0.05). CONCLUSIONS: Under the same CO2 pneumoperitoneum pressure, exposure duration was correlated with effect on maternal GH-IGF-I axis in mid- and late-pregnancy rats. Two h of exposure inhibited the GH-IGF-I axis in both mid- and late pregnancy, and therefore may restrict development of the placenta and fetus.