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Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM.

Phthalate esters are widespread in the environment. They have been described as being one of the most abundant man-made environmental contaminants that may be adverse to human health. Particularly, di-2-ethylhexyl phthalate (DEHP) has been shown to cause reproductive and developmental toxicity and is suspected to be an endocrine disruptor. The primary objective of this study is to determine the estrogenic activity of DEHP. Estrogenic activities of DEHP were studied by in vitro assays of human breast cancer MCF-7 cell proliferation. Estrogen-dependent MCF-7 cells were grown in RPMI1640 medium containing 10% fetal bovine serum. Five days before the addition of the test compounds, the cells were washed by phosphate balanced solution (PBS), and the medium was substituted with a phenol red-free RPMI1640 medium containing 5% dextral charcoalstripped Fetal Bovine Serum (FBS). Fresh medium was added to the respective test compounds and the control cell received only the vehicle (ethanol). The proliferation of MCF-7 cell was analyzed by the MTT assay, growth curves, mitotic index and colony forming efficiency. Compared with the ethanol control cells, the proliferation of tested cells treated with DEHP, like estradiol, was significantly enhanced and the activity of the cell proliferation reached the maximum at 1 6 10 23 mol/L DEHP. The relative proliferative potency of DEHP was 0.000 001 with a relative proliferative effect of 97.32%. During the log phase, the mitotic index of the tested cells treated with DEHP and estradiol was significantly increased. The cell cloning efficiency was enhanced, which was treated by 10 23 mol/L DEHP only for 48 hours. The results show a time-dependent and dose-dependent model. Di-2-ethylhexyl phthalate enhanced the proliferation of human breast cancer MCF-7 cells in vitro and might demonstrate an estrogenic activity.

Background Lung cancer remains a major cause of cancer-related mortality throughout the world at present. Repositioning of existing drugs for other diseases is a promising strategy for cancer therapies, which may rapidly advance potentially promising agents into clinical trials and cut down the cost of drug development. Ciclopirox (CPX), an iron chelator commonly used to treat fungal infections, which has recently been shown to have antitumor activity against a variety of cancers including both solid tumors and hematological malignancies in vitro and in vivo. However, the effect of CPX on non-small cell lung cancer (NSCLC) and the underlying mechanism is still unclear. Methods CCK-8, clonal formation test and cell cycle detection were used to observe the effect of inhibitor on the proliferation ability of NSCLC cells. The effects of CPX on the metastasis ability of NSCLC cells were analyzed by Transwell assays. Apoptosis assay was used to observe the level of cells apoptosis. The role of CPX in energy metabolism of NSCLC cells was investigated by reactive oxygen species (ROS) detection, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) experiments. Western blot was used to examine the protein changes. Results We report that CPX inhibits NSCLC cell migration and invasion abilities through inhibiting the epithelial-mesenchymal transition, impairing cellular bioenergetics, and promoting reactive oxygen species to activate endoplasmic reticulum (ER) stress-induced apoptotic cell death. Moreover, CPX intraperitoneal injection can significantly inhibit NSCLC growth in vivo in a xenograft model. Conclusions Our study revealed that CPX targets cellular bioenergetics and activates unfolded protein response in ER to drive apoptosis in NSCLC cells, indicating that CPX may be a potential therapeutic drug for the treatment of NSCLC. Graphical Abstract