Planta Med 2015; 81 - SL3B_02
DOI: 10.1055/s-0035-1565315

Xanthones from the bitter plants Gentiana lutea, Centaurium erythraea, and Frasera caroliniensis (Gentianaceae) inhibit vascular smooth muscle cell (VSMC) proliferation

B Waltenberger 1, R Liu 2, AG Atanasov 2, S Schwaiger 1, EH Heiss 2, VM Dirsch 2, H Stuppner 1
  • 1Institute of Pharmacy/Pharmacognosy, University of Innsbruck, Innsbruck, Austria
  • 2Department of Pharmacognosy, University of Vienna, Vienna, Austria

Excessive proliferation of vascular smooth muscle cells (VSMC) plays a major role in cardiovascular disease and greatly contributes to restenosis, the recurrence of blood vessel constriction after surgical treatment of stenosis. Due to unfavourable side effects of available pharmaceuticals, the discovery of new inhibitors of VSMC proliferation is of great importance.

A natural product screening approach using a resazurin conversion assay led to the identification of a xanthone derivative as inhibitor of VSMC proliferation. In order to potentially find further active compounds and to gain more information about the structure activity relationship (SAR), 13 additional xanthone derivatives isolated from three bitter plants from the Gentianaceae family (Gentiana lutea, Centaurium erythraea, and Frasera caroliniensis) [1] were also tested. Whereas some compounds showed no or moderate activity when applied at 30 µM, the four most active xanthones showed IC50 values between 7.8 and 12.5 µM. Their anti-proliferative effect was confirmed by measuring DNA synthesis in VSMC by quantification of 5-bromo-2′-deoxyuridine (BrdU) incorporation into DNA. In this model, the four xanthones exhibited IC50 values in the range 5.7 – 24.5 µM. Cell death quantification (LDH assay) revealed that they are not cytotoxic in the tested concentration range.

In conclusion, our study identifies xanthones as new scaffold VSMC proliferation inhibitors that might be of relevance as a starting point for the development of new therapeutic applications to combat restenosis.

Acknowledgement: Supported by the TWF, the FWF (NFN-S10703, NFN-S10704, P25971-B23, and P23317-B11), the EU-FP7 Marie Curie Fellowship 252881, and the University of Vienna “Back-to-Research Grant”.

References:

[1] Aberham A, Pieri V, Croom EM Jr, Ellmerer E, Stuppner H. Analysis of iridoids, secoiridoids and xanthones in Centaurium erythraea, Frasera caroliniensis and Gentiana lutea using LC-MS and RP-HPLC. J Pharm Biomed Anal 2011; 54: 517 – 525