INDUCTION OF APOPTOSIS IN SMALL BOWEL CARCINOID CELLS BY NOVEL BIOACTIVE AGENTS DERIVED FROM TRAILLIAEDOXA GRACILIS (WW SMITH & FORREST)

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Svejda B.1, Aguiriano MoserV.1, Modlin I.M.2, Siegl V.1, Ingolic E.3, Sturm S.4, Stuppner H.4, Pfragner R.1
1 Department of Pathophysiology & Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria; 2Department of Surgery, Yale University School of Medicine, New Haven Connecticut, USA; 3Research Institute for Electron Microscopy & Finestructure Research, Technical University of Graz, Graz, Austria; 41nstitute of Pharmacy, Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
Background: Carcinoids of the gastrointestinal tract are rare, slowly proliferating tumors derived from enterochromaffin or Kulchitsky's cells; they are often difficult to diagnose and incurable when metastatic. The medical treatment of these neuroendocrine tumors focuses on surgical excision and the use of somatostatin analogs to secure control of both symptoms and proliferation. As a significant number of patients are non-responsive and inoperable at time of diagnosis, new therapeutic options have been sought.

The aim of our investigation was to evaluate whether different extracts and fractions of Trailliaedoxa gracilis (WW Smith & Forrest) (TG) had effects on proliferation, morphology and/or apoptotic rates in cultured carcinoid cells. Methods: Based on a continuous human cell line established from a malignant carcinoid of the small bowel- KRJ1*) – the effects of five different fractions of TG were tested. Morphology of treated cells was studied by electron microscopy; proliferation and viability were quantified by cell counts and WSt-1 cytotoxicity assays. Apoptosis was determined by DAPI-staining and luminescent assays for caspases 3/7, 8, 9, 2 and 6 were performed.

Results: showed a dose-dependent reduction of proliferation and a significant induction of apoptosis in TG-treated KRJ-I cells without impairing normal cells.

Conclusion: These data suggest that TG-fractions may be used as highly specific compounds for the therapy of carcinoids.

Pfragner R et al. Establishment of a continuous cell line from a human carcinoid of the small intestine (KRJ-I): Characterization and effects of 5-azacytidine on proliferation. Int J Onco/8:513520,1996.
Modlin 1M, Kidd, Pfragner R, Eick GN, Champaneria Me. The functional characterization of normal and neoplastic human enterochromaffin cells. J Clin Endocrinol Metab 91 :2340-2348,2006.