Non-steroidal antiestrogens induce apoptosis in HL60 and MOLT3 leukemic cells; involvement of reactive oxygen radicals and protein kinase C.
The antitumoral activity of non-steroidal antiestrogens on promyelocytic leukemia HL60 and T lymphoblastic MOLT3 cell lines was studied. Tamoxifen and its derivatives, clomiphene and nafoxidine, caused reduction of cell viability in a dose-dependent manner. These drugs showed differences in their potency following four days incubation, with nafoxidine being the most efficient inhibitor and tamoxifen the least active. Apoptosis was induced as assessed by the DNA ladder pattern and formation of pre G0/G1 population as detected by flow cytometry analysis of DNA. The effect of these drugs was abrogated by antioxidants: alpha-tocopherol was most effective in antagonizing the drugs' effect. N-acetyl L-cysteine reversed mainly the decrease in cell viability caused by the drugs, but was less active on induction of apoptosis. GF109203X, a protein kinase inhibitor, attenuated apoptosis induced by clomiphene in MOLT3 cells. The results suggest that the antileukemic activity of the antiestrogens is mediated by oxidative stress and protein kinase C (PKC) activation. Triphenylethylene antiestrogens and their derivatives may be used as antileukemic drugs which kill cells by apoptosis mediated by oxidative stress and activation of PKC.
Hayon
T
T
Department of Clinical Biochemistry, Faculty of Health Sciences, Soroka Medical Center, Beer Sheva, Israel.
Dvilansky
A
A
Oriev
L
L
Nathan
I
I
D000111:Acetylcysteine / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002996:Clomiphene / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008301:Maleimides / Q000494:pharmacology; D009256:Nafoxidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D017382:Reactive Oxygen Species; D013629:Tamoxifen / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D007211:Indoles; D008301:Maleimides; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D014810:Vitamin E; D002996:Clomiphene; D009256:Nafoxidine; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D000111:Acetylcysteine