Clin Cancer Res. 2008 Sep 1;14(17):5519-30.
therapy of hepatoma with artemisinin and its derivatives: in vitro and
in vivo activity, chemosensitization, and mechanisms of action.
Hou J, Wang D, Zhang R, Wang H.
Laboratory of Nutrition and Metabolism, Institute for Nutritional
Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy
of Sciences; Graduate School of the Chinese Academy of Sciences,
Shanghai 200031, People's Republic of China.
ART and its derivatives, clinically used antimalarial agents, have
recently shown antitumor activities. However, the mechanisms underlying
these activities remain unclear. This study was designed to determine
their antitumor efficacy and underlying mechanisms of action in human
EXPERIMENTAL DESIGN: The in vitro cytotoxicities of
ART, DHA, artemether, and artesunate were compared in human hepatoma
cells, HepG2 (p53 wild-type), Huh-7 and BEL-7404 (p53 mutant), and
Hep3B (p53 null), and a normal human liver cell line, 7702. Based on
their activity and specificity, ART and DHA were further investigated
for their in vitro and in vivo antitumor effects and their effects on
the protein expression of genes associated with cell proliferation and
RESULTS: ART and DHA exerted the greatest cytotoxicity to
hepatoma cells but significantly lower cytotoxicity to normal liver
cells. The compounds inhibited cell proliferation, induced G(1)-phase
arrest, decreased the levels of cyclin D1, cyclin E, cyclin-dependent
kinase 2, cyclin-dependent kinase 4, and E2F1, and increased the levels
of Cip1/p21 and Kip1/p27. They induced apoptosis, activated caspase-3,
increased the Bax/Bcl-2 ratio and poly(ADP-ribose) polymerase, and
down-regulated MDM2. In mice bearing HepG2 and Hep3B xenograft tumors,
ART and DHA inhibited tumor growth and modulated tumor gene expression
consistent with in vitro observations. DHA increased the efficacy of
the chemotherapeutic agent gemcitabine.
CONCLUSIONS: ART and DHA have
significant anticancer effects against human hepatoma cells, regardless
of p53 status, with minimal effects on normal cells, indicating that
they are promising therapeutics for human hepatoma used alone or in
combination with other therapies.