(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose dependently inhibited by EGCG at doses of 0.1, 0.3 and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose dependently reduced by EGCG; the estimated concentration that causes 50% inhibition (IC(50)) (20 microM) was much higher than the IC(50) (0.15 microM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vivo and in vitro in the described experimental system.
Philadelphia chromosome-positive (Ph+) AML is a controversial diagnosis,
as others propose it represents CML in blast phase (CML-BP).
NPM1 mutations occur in 25-35% of AML but are absent in CML
patients. Conversely, ABL1 mutations occur in 25% of
Imatinib-naïve CML-BP but are not described in AML patients. We analyzed
for NPM1 and ABL1 mutations in 9 Ph+ AML and 5
CML-BP patients initially presented in BP. In 6 Ph+ AML cases, we screened for a
panel of gene mutations using Sequenome®-based methods including
AKT1, AKT2, AKT3, BRAF,
EGFR, GNAQ, GNAS,
IDH1, IDH2, KRAS,
MET, NRAS, PIK3CA, and
RET. Two of 9 (22%) Ph+ AML patients had
NPM1 mutations and were alive 36 and 71 months after
diagnosis. All Ph+ AML were negative for ABL1 and other gene
mutations. One (20%) CML-BP patients had ABL1 mutation; no
patients had NPM1 mutations. These data suggest that Ph+ AML is
distinct from CML-BP.
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