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 prostate cancer patients. We have invest igated the potency of tributyrin, an orally available prodrug of butyrate, to induce growth arrest, differentiation and apoptosis in LNCaP, PC-3 and T SU-PR1 human prostate cancer cell lines. Cells were treated with 0.1 to 5 m M tributyrin or sodium butyrate, Growth inhibition, cell cycle arrest and a poptosis 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 anti gen was increased in LNCaP cells by tributyrin as a indicator of differenti ation. The IC50 for sodium butyrate was 2.5 mM in PC-3 and TSU-PR1 cells. L NCaP cells exhibited <50% growth inhibition at 5 mM sodium butyrate, Howeve r, the IC50 for tributyrin was 0.8 mM in PC-3 cells, 1.2 mM in TSU-PR1 cell s and 3.1 mM in LNCaP cells, Flow cytometry revealed a strong G1-arrest aft er exposure to tributyrin or sodium butyrate. Both agents resulted in a str ong increase of apoptosis rates compared with mock-treated cells. Overall, tributyrin had a 2.5- to 3-fold growth inhibitory and apoptosis-inducing po tency compared with equimolar concentrations of sodium butyrate, Our result s demonstrate that tributyrin is more potent than butyrate in regard to cel l growth inhibition and apoptosis induction at pharmacologically relevant c oncentrations. Hence, tributyrin may be a promising candidate for clinical protocols in prostate cancer. Int. J. Cancer 88:245-251, 2000, (C) 2000 Wil ey-Liss, Inc.