Cytotoxic effects of 2-methoxyestradiol in the hepatocellular carcinoma cell line HepG2.
OBJECTIVE
The study was designed to examine the potential cytotoxicity of 2-methoxyestradiol (2ME2), a natural 17beta-estradiol metabolite, in hepatocellular carcinoma and the possible underlying mechanisms for this cytotoxicity.


METHODS
The cell line HepG2 was treated with different concentrations of 2ME2 for 48 and 72 h.


RESULTS
Using the sulforhodamine B assay, HepG2 was sensitive to the cytotoxic effect of 2ME2. 2ME2 induced cell arrest at the G(2)/M phase and a significant high percentage of apoptotic cells compared to the control group. Also, 2ME2 induced a significant increase in caspase 9 enzymatic activity after 48 and 72 h of treatment compared with control values. The DNA laddering was observed only in cells treated for 72 h. Furthermore, 2ME2 induced a significant decrease in the expression levels of vascular endothelial growth factor (VEGF) gene compared to the control values.


CONCLUSIONS
2ME2 exerts cytotoxic activity in the HepG2 cell line by preferential cell blocking at the G(2)/M phase as well as induction of apoptosis as evidenced by increased caspase 9 enzymatic activity and observed DNA laddering in 2ME2-treated HepG2 cells. In addition, a reduction in hypervascularity is an important postulated mechanism as indicated by the significant reduction in the expression of VGEF, one of the most important angiogenic factors.
El Naga
Reem N Abou
RN
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
El-Demerdash
Ebtehal
E
Youssef
Samar S
SS
Abdel-Naim
Ashraf B
AB
El-Merzabani
Mahmoud
M
D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077584:2-Methoxyestradiol; D053453:Caspase 9