Developing therapeutic approaches for BHD syndrome

A large part of BHD research focuses on elucidating the role of folliculin in the cell and understanding the effects of folliculin loss. Another important aspect of BHD research is developing therapeutic treatments for BHD syndrome, and in particular for renal cell carcinoma (RCC). In light of this, a recent paper by Lu et al. (2011) describes advances in identifying potential therapies for RCC.

Lu et al. (2011) set about identifying compounds that selectively inhibit tumour growth in RCC cell lines that have FLCN inactivation. Potential drugs were initially identified using the DTP COMPARE algorithm and the NCI-60 panel of 60 cancerous cell lines. For each cell line, the toxicity of each compound in the DTP database was compared with the FLCN expression level. Drugs to which cell lines with low FLCN expression were most sensitive and also cell lines with high FLCN expression were most resistant were selected for further analysis.

The 15 compounds identified by the COMPARE algorithm were then screened in UOK257 cells, with and without FLCN, using a growth inhibition assay. Compounds which inhibited the growth of FLCN-/- cells but had little effect on FLCN+/+ cells were identified by GI50 values (the concentration of compound required to inhibit growth by 50%). Mithramycin was identified as being the most selective compound, with a 10-fold difference in GI50 value between FLCN-/- and FLCN+/+ cells.

Mithramycin also showed differential caspase 3/7 activity between FLCN-/- and FLCN+/+ cells, with an 8-fold higher activity in UOK FLCN-/- cells. This indicates a higher rate of apoptosis in cells that lack FLCN. Cell viability assays and cytotoxicity assays also produced consistent results that suggest mithramycin is selectively cytotoxic for UOK FLCN-/- cells over UOK FLCN+/+ cells.

Mithramycin binds to GC-rich regions of DNA and inhibits transcription. It has been used to treat several types of cancer through its inhibition of Sp1 expression, a transcription factor involved in cancer angiogenesis (Yuan et al, 2007). The mode of action of mithramycin in UOK cells is unclear as no inhibition of Sp1 was observed in either cell line. More work is required to assess whether mithramycin could be developed as a therapy for RCC in BHD syndrome.

 

  • Lu X et al. Therapeutic targeting the loss of the Birt-Hogg-Dubé suppressor gene. Mol Cancer Ther. 2011 Jan;10(1):80-9.
  • Yuan P et al. Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer. 2007 Dec 15;110(12):2682-90.

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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