Inhibition by arsenic trioxide of human hepatoma cell growth.
Arsenic trioxide (As(2)O(3)) has been shown to be effective for treatment of patients with refractory or relapsed acute promyelocytic leukemia and a variety of other malignant hematopoetic disorders. We studied the effect of this agent on proliferation of human hepatoma-derived cell lines (SK-Hep-1, HepG2, and HuH7). In HuH7 cells, As(2)O(3) reduced proliferation time- and dose-dependently at 1 and 2 microM, while in SK-Hep-1 and HepG2 cells, As(2)O(3) inhibited proliferation at 2 and 4 microM respectively. Cell cycle analysis by flow cytometry showed that As(2)O(3) induced apoptosis in these hepatoma-derived cells as confirmed by appearance of sub-G(1) cells. Sensitivity of hepatoma-derived cells to As(2)O(3) was inversely related to their intracellular glutathione (GSH) and intensity of GSH synthesis. Arsenic sensitivity was restored to relatively resistant cell lines when GSH was depleted by L-buthionine sulfoximine (BSO). These results indicate that As(2)O(3) may have therapeutic potential for treatment of hepatocellular carcinoma.
Oketani
Makoto
M
The Second Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. oketani@m2.kufm.kagoshima-u.ac.jp
Kohara
Kazunori
K
Tuvdendorj
Demidmaa
D
Ishitsuka
Kenji
K
Komorizono
Yasuji
Y
Ishibashi
Kazuaki
K
Arima
Terukatsu
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D004396:Coloring Agents; D010087:Oxides; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D005978:Glutathione; D000077237:Arsenic Trioxide