Tributyrin induces differentiation, growth arrest and apoptosis in androgen-sensitive and androgen-resistant human prostate cancer cell lines

Progression to androgen independence remains the main problem that impacts on survival and quality of life in prostare cancer patients. We have investigated the potency of tributyrin, an orally available prodrug of butyrate, to induce growth arrest, differentiation and apoptosis in LNCaP, PC-3 and TSU-PRI human prostate cancer cell lines. Cells were treated with 0.1 to 5 mM tributyrin or sodium butyrate. Growth inhibition, cell cycle arrest and apoptosis induction was assessed using standard methods. Both agents induced a more differentiated, fibroblast-like phenotype in androgen-sensitive as well as androgen-resistant cell lines. Expression of prostate-specific antigen was increased in LNCaP cells by tributyrin as a indicator of differentiation. The IC₅₀ for sodium butyrate was 2.5 mM in PC-3 and TSU-PRI cells. LNCaP cells exhibited <50% growth inhibition at 5 mM sodium butyrate. However, the IC₅₀ for tributyrin was 0.8 mM in PC-3 cells, 1.2 mM in TSU-PRI cells and 3,1 mM in LNCaP cells. Flow cytometry revealed a strong GI-arrest after exposure to tributyrln or sodium butyrate. Both agents resuited in a strong increase of apoptosis rates compared with mock-treated cells. Overall, tributyrin had a 2.5- to 3-fold growth inhibitory and apoptosis-inducing potency compared with equimolar concentrations of sodium butyrate. Our results demonstrate that tributyrin is more potent than butyrate in regard to cell growth inhibition and apoptosis induction at pharmacologically relevant concentrations. Hence, tributyrin may be a promising candidate for clinical protocols in prostate cancer. (C) 2000 Wiley-Liss, Inc.