مـي
01-08-2007, 11:38 PM
بليز احد يساعدي بترجمة ذا النص الترجمه الإليكترونيه مو نافعه sqsqsq
HIF as therapeutic !!!!!!
Tran!!!!!!ion factors are difficult !!!!!!s for anti-cancer drug discovery as they are not enzymes for the identification of active site inhibitors. Given the overexpression of HIF-1 in so many tumor types and association of HIF-1 with tumor angiogenesis, many approaches have been taken to identify agents that reduce HIF-1 protein levels (Dachs et al. 1997, Semenza 2002, 2003, Binley et al. 2003, Carroll & Ashcroft 2005). An example of one such drug, PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino] phenyl propionic acid N-oxide dihydrochloride) inhibits the accumulation of HIF-1 and reduces HIF-1 activity (Wiedmann & Caca 2005). High throughput HIF-1 reporter gene assays have been used to start to screen diverse chemical and natural product libraries (Tan et al. 2005).
Other groups have sought disruption of HIF-1 upstream signaling by attacking RAS-related proteins. Using radio-resistant human U87 glioblastoma (GBM) and a specific farnesyltransferase inhibitor R115777, Delmas et al.(2003) showed reduced matrix ****lloproteinase 2 activities and reduced hypoxic-regulated signaling. Another group of investigators showed that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound anti-oncogenic effects in U87 GBM cells. FTS inhibited active Ras and its signaling to phosphatidylinositol-3-kinase and Akt pathway; hence, HIF-1 was lowered and downstream HIF-regulated genes were affected (Blum et al. 2005).
Another upstream approach to inhibit HIF-1 in normoxic tumors utilizes the anti-epidermal growth factor receptor monoclonal anti!!!! cetuximab (C225; Erbitux), which is approved for the treatment of ****static colorectal cancer. This monoclonal anti!!!! has been known to inhibit VEGF secretion in vitro and in vivo. Studies show that cetuximab reduces HIF-1 in epidermoid carcinoma cells under both normoxic and hypoxic conditions. This inhibition is through the RAS pathway and confirms that VEGF secretion can be modulated by signal transduction inhibition of HIF-1 protein translation (Luwor et al. 2005).
In addition to monoclonal antibodies, compounds that share a 2,2-dimethylbenzopyran structural motif have been shown to inhibit hypoxia-induced tran!!!!!!ion activity. Small molecule 103D5R markedly decreased HIF-1 protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner. 103D5R was shown to inhibit the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH(2)-kinase, proving worthy of continued investigation of the drug as a HIF-1 inhibitor (Tan et al. 2005).
HIF-1 inhibitors are also in clinical trials of breast and prostate cancer. 2-Methoxyestradiol (2ME2) is an estradiol ****bolite with significant anti-proliferative and anti-angiogenic activity independent of estrogen receptor status; it is currently in clinical trials (Panzem:Entrre Med) and in vivo it has been shown to inhibit tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) (Mabjeesh et al. 2003a, Ricker et al. 2004). 2ME2 down regulates HIF-1 at the post-tran!!!!!!ional level and inhibits HIF-1-induced tran!!!!!!ional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-1 downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton with drugs, such as taxol and taxotere and inhibition of angiogenesis (Mabjeesh et al. 2003b).
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be good candidates for chemoprevention agents because, in part, of their anti-angiogenic properties on precancerous lesions. As a class of agents, cyclo-oxygenase inhibitors appear to downregulate HIF-1. The inhibition of HIFs by NSAIDs was COX-2 independent (Jones et al. 2002, Palayoor et al. 2003, Zhong et al. 2004b). A more comprehensive list of anti-neoplastic/anti-angiogenic agents that are reported to affect HIF-1
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HIF as therapeutic !!!!!!
Tran!!!!!!ion factors are difficult !!!!!!s for anti-cancer drug discovery as they are not enzymes for the identification of active site inhibitors. Given the overexpression of HIF-1 in so many tumor types and association of HIF-1 with tumor angiogenesis, many approaches have been taken to identify agents that reduce HIF-1 protein levels (Dachs et al. 1997, Semenza 2002, 2003, Binley et al. 2003, Carroll & Ashcroft 2005). An example of one such drug, PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino] phenyl propionic acid N-oxide dihydrochloride) inhibits the accumulation of HIF-1 and reduces HIF-1 activity (Wiedmann & Caca 2005). High throughput HIF-1 reporter gene assays have been used to start to screen diverse chemical and natural product libraries (Tan et al. 2005).
Other groups have sought disruption of HIF-1 upstream signaling by attacking RAS-related proteins. Using radio-resistant human U87 glioblastoma (GBM) and a specific farnesyltransferase inhibitor R115777, Delmas et al.(2003) showed reduced matrix ****lloproteinase 2 activities and reduced hypoxic-regulated signaling. Another group of investigators showed that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound anti-oncogenic effects in U87 GBM cells. FTS inhibited active Ras and its signaling to phosphatidylinositol-3-kinase and Akt pathway; hence, HIF-1 was lowered and downstream HIF-regulated genes were affected (Blum et al. 2005).
Another upstream approach to inhibit HIF-1 in normoxic tumors utilizes the anti-epidermal growth factor receptor monoclonal anti!!!! cetuximab (C225; Erbitux), which is approved for the treatment of ****static colorectal cancer. This monoclonal anti!!!! has been known to inhibit VEGF secretion in vitro and in vivo. Studies show that cetuximab reduces HIF-1 in epidermoid carcinoma cells under both normoxic and hypoxic conditions. This inhibition is through the RAS pathway and confirms that VEGF secretion can be modulated by signal transduction inhibition of HIF-1 protein translation (Luwor et al. 2005).
In addition to monoclonal antibodies, compounds that share a 2,2-dimethylbenzopyran structural motif have been shown to inhibit hypoxia-induced tran!!!!!!ion activity. Small molecule 103D5R markedly decreased HIF-1 protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner. 103D5R was shown to inhibit the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH(2)-kinase, proving worthy of continued investigation of the drug as a HIF-1 inhibitor (Tan et al. 2005).
HIF-1 inhibitors are also in clinical trials of breast and prostate cancer. 2-Methoxyestradiol (2ME2) is an estradiol ****bolite with significant anti-proliferative and anti-angiogenic activity independent of estrogen receptor status; it is currently in clinical trials (Panzem:Entrre Med) and in vivo it has been shown to inhibit tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) (Mabjeesh et al. 2003a, Ricker et al. 2004). 2ME2 down regulates HIF-1 at the post-tran!!!!!!ional level and inhibits HIF-1-induced tran!!!!!!ional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-1 downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton with drugs, such as taxol and taxotere and inhibition of angiogenesis (Mabjeesh et al. 2003b).
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be good candidates for chemoprevention agents because, in part, of their anti-angiogenic properties on precancerous lesions. As a class of agents, cyclo-oxygenase inhibitors appear to downregulate HIF-1. The inhibition of HIFs by NSAIDs was COX-2 independent (Jones et al. 2002, Palayoor et al. 2003, Zhong et al. 2004b). A more comprehensive list of anti-neoplastic/anti-angiogenic agents that are reported to affect HIF-1
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