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

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.

Involvement of p53 and Nuclear Factor-kappaB Signaling Pathway for the Induction of G1-Phase Cell Cycle Arrest of Cholangiocarcinoma Cell Lines by Isomorellin

“…51) Dulxanthone A-an active cytotoxic xanthone isolated from Garcinia cowa ROXB (family Guttiferae)-induced cell cycle arrest and apoptosis via up-regulation of p53 through mitochondrial pathway in HepG2 cells. 52) An increased accumulation of nuclear NF-κB in the bile duct epithelial cells of Opisthorchis viverrini-infected hamsters is hypothesized to play an important role in inflammation-associated CCA development. 11) Relatedly, a high expression of NF-κB (p50, p52 and p65) was found in 100% (58 cases) of CCA patients' tissues compared with normal cholangiocytes from cadaveric donors (Seubwai et al, manuscript in preparation).…”

Cytostatic response of HepG2 to 0.57 MHz electric currents mediated by changes in cell cycle control proteins

“…Drugs such as flavopiridol or the proteasome inhibitor PS-341 induce decreased levels of cyclins D1, A and B, and arrest cells in the G1 to S phase transition, in S phase or in the G2 to M transition (44). Recent studies have reported that drugs like dulxanthone A induce apoptosis by blocking the S phase of cell cycle in the line HepG2 (45). Thus, the herein reported results indicate that in vitro treatment with CRet currents could induce effects that mimic the cellular response to chemicals with potential applications in oncology.…”

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

“…The mitochondrial pathway of apoptosis functions in response to various types of stress. A variety of chemotherapeutic agents trigger apoptosis in susceptible cells by inducing MMP disruption, followed by release of cytochrome c, which interacts with the cytosolic docking protein, thereby facilitating activation of procaspase-9 and subsequent proteolytic processing of procaspase-3 and procaspase-7 [24][25][26] . Once activated, these caspases cleave and activate downstream effector caspases (including 3, 6, and 7), which in turn cleave cytoskeletal and nuclear proteins like PARP, DFF and lamin A, and induce apoptosis.…”