Ciclopirox olamine (CPX) is a synthetic antifungal agent clinically used to treat mycoses of the skin and nails. Here, we show that CPX inhibited tumor growth in human breast cancer MDA-MB-231 xenografts. To unveil the underlying mechanism, we further studied the antitumor activity of CPX in cell culture. The results indicate that CPX inhibited cell proliferation and induced apoptosis in human rhabdomyosarcoma (Rh30), breast carcinoma (MDA-MB231) and colon adenocarcinoma (HT-29) cells in a concentration-dependent manner. By cell cycle analysis, CPX induced accumulation of cells in G 1 /G 0 phase of the cell cycle. Concurrently, CPX downregulated cellular protein expression of cyclins (A, B1, D1 and E) and cyclin-dependent kinases (CDK2 and CDK4) and upregulated expression of the CDK inhibitor p21Cip1 , leading to hypophosphorylation of retinoblastoma protein. CPX also downregulated protein expression of Bcl-xL and survivin and enhanced cleavages of Bcl-2. Z-VAD-FMK, a pan-caspase inhibitor, partially prevented CPX-induced cell death, suggesting that CPX-induced apoptosis of cancer cells is mediated at least in part through caspase-dependent mechanism. The results indicate that CPX is a potential antitumor agent.Ciclopirox olamine (CPX) (also called Batrafen, Loprox, Penlac and Stieprox), the ethanolamine salt of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, is a synthetic antifungal agent used to treat mycoses of the skin and nails for more than 20 years. 1-3Studies have shown that CPX has a very broad spectrum of action against dermatophytes, yeast, filamentous fungi and bacteria. 4,5 The mechanisms of these actions of CPX seem diverse, involving disruption of membrane function in fungi or targeting different metabolic (respiratory) and energy-producing processes in bacteria.1,2 In the yeast Saccharomyces cerevisiae, CPX may also exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.6 Apart from its antimycotic and antibacterial activities, CPX arrests the cell cycle at G 1 phase in mammalian cells 7,8 and G 2 /M phase in the yeast S. cerevisiae. 9 CPX also prevents the death of tropic factor-deprived PC12 cells and postmitotic sympathetic neurons by blocking the cell cycle progression 7 or the death of cerebellar granule neurons in low K þ -containing medium, 10 but it induces an active cell death in S. cerevisiae. 9In addition, CPX is a well-known iron chelator, inhibiting the iron-containing enzymes, such as catalase and peroxidase.11 Most recent studies have revealed that the chelation of intracellular iron and the inhibition of the iron-dependent enzyme ribonucleotide reductase were associated with CPXinduced cell death.12 It appeared that CPX induced cell death in primary human acute myeloid leukemia (AML) cells and inhibited engraftment of primary AML cells in NOD/SCID mouse models without gross organ toxicity or loss of body weight.12 Previous safety and toxicity studies of CPX also demonstrated that a 4-w...

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G 1 -G 0 phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I-or 10% fetal bovine serum-stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration-and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent. Cancer Prev Res; 3(8); 1015-25. ©2010 AACR.

BackgroundMigration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated.Methods and ResultsMDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK.ConclusionDATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.