Effects of a novel antitumor depsipeptide, FR901228, on human breast cancer cells

Human breast cancer MCF7 and MDA-MB231 cells were used to investigate the biological and molecular activities of a novel naturally occurring agent, FK901228 (FK), that possesses a potent antitumor activity against hum an and murine tumor cells. Investigation of the cytotoxicity of FR and induction of internucleosomal DNA degradation in FR-treated cultures revealed that FR induced apoptotic-like cell death of MCF7 and MDA-MB231 cells. In FR-treated apoptotic cultures, flow cytometry? revealed that there was a significant decrease of cells in S phase of the cell cycle. In FK-treated ce Ils there was an increased expression of p21(Cip1) and phosphorylation of Bcl-2 as determined by Western immunoblotting, and a novel cytoplasmic kinase of 33 kDa, p33 kinase, as determined by the in-gel kinase assay using myelin basic protein (MBP) as a substrate. Increased expression of P21(Cip1) phosphorylation of Bcl-2 and activation of p33 MBP kinase may play part of the key mechanism for FR-induced apoptosis.