Molecular pathology of Birt-Hogg-Dubé Syndrome

[摘要] Autosomal dominantly inherited mutations in the folliculin (FLCN) gene lead to Birt-Hogg-Dubé syndrome (BHD), which is associated with increased risk of kidney cancer. With the aim of better understanding and treating BHD and its associated renal cell carcinoma (RCC) this study analyzes the potential use of tumour growth inhibitors selective for FLCN-defective cells. Fifteen compounds have been initially selected using the COMPARE algorithm from the chemotherapeutic compounds tested in the NCI-60 cell lines panel based on the highest toxicity in the cell lines with low level of FLCN expression. Growth inhibition assays performed in a paired RCC cell lines with and without active FLCN confirmed that seven compounds decreased growth in FLCN-null cells compared with FLCN-wt cells. The greatest inhibitory selectivity was induced by mithramycin in which a 10-fold difference between GI50 values in FLCN negative and positive UOK257 cells. Mithramycin was also shown to be more cytotoxic to FLCN negative cells than to FLCN-positive UOK257 cells by 10 fold (at 200nM), in clonogenic survival assays. Low doses of rapamycin (1 nM) further increased mithramycin's inhibitory selectivity for FLCN mutant UOK cells, encouraging further investigation of mithramycin as a molecularly-targeted therapy for RCC in BHD.

[发布机构] University:University of Birmingham;Department:School of Clinical and Experimental Medicine

[关键词] R Medicine;R Medicine (General)