Dulxanthone A induces cell cycle arrest and apoptosis via up‐regulation of p53 through mitochondrial pathway in HepG2 cells

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Abstract
Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity‐directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up‐regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc‐2, p21 and p27 were down‐regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl‐2 family members PUMA was up‐regulated while Bcl‐2 and Bax were down‐regulated. However, the expression ratio of Bax/Bcl‐2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf‐1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf‐1 and procaspase‐9 form an apoptosome, which in turn triggered the activation of caspase‐9, caspase‐3 and downstream caspase substrates. Lamin A/C and PARP were down‐regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up‐regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma.