Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma CellsReportar como inadecuado




Anti-Cancer Potential of MAPK Pathway Inhibition in Paragangliomas–Effect of Different Statins on Mouse Pheochromocytoma Cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

To date, malignant pheochromocytomas and paragangliomas PHEOs-PGLs cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells MPC and the more aggressive mouse tumor tissue-derived cells MTT, which was accompanied by decreased phosphorylation of mitogen-activated kinase MAPK pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs-PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase SDH B mutation-derived PHEOs-PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs-PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.



Autor: Stephanie M. J. Fliedner , Tobias Engel , Nikoletta K. Lendvai, Uma Shankavaram, Svenja Nölting, Robert Wesley, Abdel G. Elkahlo

Fuente: http://plos.srce.hr/



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