Malignant tumors remain a significant health threat, with death often occurring as a result of metastasis. Cell adhesion is a crucial step in the metastatic cascade of tumor cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Celastrol [3-hydroxy-24-nor-2-oxo-1(10),3,5,7-friedelatetraen-29-oic acid], a quinone methide triterpene from the medicinal plant Tripterygium wilfordii, possesses antitumor activities, whereas the underlying mechanism(s) remains elusive. Here, we found that celastrol inhibited cell-extracellular matrix (ECM) adhesion of human lung cancer 95-D and mouse melanoma B16F10 cells. This inhibition was achieved through suppressing 1 integrin ligand affinity and focal adhesion formation, accompanied by the reduced phosphorylation of focal adhesion kinase (FAK). In understanding the underlying mechanisms, we found that celastrol activated p38 mitogen-activated protein kinase (MAPK) by phosphorylation before the decrement of phosphorylated FAK and that this action was independent of the presence of fibronectin. Using 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAPK, the effects of celastrol on 1 integrin function, cell-ECM adhesion, and phosphorylation of FAK were partially attenuated. In addition, focal adhesion-dependent cell migration and invasion were both inhibited by treatment with celastrol. Finally, the antimetastatic activity of celastrol was examined in vivo using the B16F10-green fluorescent proteininjected C57BL/6 mouse model, as indicated by decreased pulmonary metastases in celastrol-administrated mice. Taken together, these data demonstrate for the first time that celastrol exerts potent antimetastatic activity both in vitro and in vivo, and they provide new evidence for the critical roles of p38 MAPK in the regulation of integrin function and cell adhesion.The maintenance, promotion, and disruption of cell adhesion are particularly important in cancer progression and metastasis. Adhesion occurs not only in malignant cell detachment from the primary carcinoma but also in tumor cell attachment to distant tissue, and multiple cell adhesion molecules are involved in these events (Pascho et al., 2009). In the former case, adhesion between cell and cell is downregulated, and classic cadherin molecules such as E-cadherin are linked to the actin cytoskeleton through linker molecules, including ␣-or -catenin (Lorch et al., 2007). In the latter case, cell surface molecules mediate the cell-extracellular matrix (ECM) attachment. Among these molecules, integrin clusters, the most important molecules, are responsible for forming a stable membrane platform with a high avidity for the ECM on the outside of the cell; and on the inside of the cell, they have multiple binding sites for adaptors and enzymes that become compartmentalized into plasma membrane-associated complexes (Streuli and Akhtar, 2009). Accordingly, owing to its initial roles in cance...
Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1a (HIF-1a) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1a expression by decreasing HIF-1a protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1a protein, decreased the HIF-1a transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1a is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1a is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers. Mol Cancer Ther; 13(3); 630-42. Ó2013 AACR.
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