Initiation of growth arrest and apoptosis of MCF-7 mammary carcinoma cellsby tributyrin, a triglyceride analogue of the short-chain fatty acid butyrate, is associated with mitochondrial activity

we investigated the effects of tributyrin, a triglyceride analogue of the s hort-chain fatty acid butyrate and an approved food additive, establishing induction of growth arrest and apoptosis of MCF-7 human mammary carcinoma c ells. Transient increased mitochondria-associated bar, dissipation of the m itochondrial membrane potential (Delta Psi(m)), and caspase-3-independent c leavage of poly(ADP-ribose) polymerase are evident as early as 4 h after tr eatment of cells with tributyrin. These events are followed by the transien t accumulation of mitochondrial cytochrome c in the cytosol and, finally, t he generation and accumulation of cells with subdiploid DNA content. During the period in which mitochondria-associated bar levels are elevated, the D elta Psi(m) is disrupted, and cytochrome c is detected in the cytosol, we s how induction of p21(WAF1/Cip1) the absence of increased p53 and arrest of cells in G(2)-M. Thus, early mitochondria-associated events may play a key role in initiating and/or coordinating tributyrin-mediated growth arrest an d apoptosis of wild-type p53 MCF-7 cells. Because effective chemoprevention has been associated with agents that restore or maintain the balance betwe en proliferation and apoptosis, dietary tributyrin, particularly during the critical period of mammary gland development, may be a promising chemoprev entive agent.