Antiproliferative properties of aminosteroid antioxidants on cultured cancer cells.
The antiproliferative properties of three 21-aminosteroid antioxidants (lazaroids), 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1- piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione, hydrochloride (U74500A), 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piper- azinyl]-pregna-1,4,9(11)-triene-3,20-dione, monomethanesulfonate (U74389F), 2H-1-benzopyran-6-ol, 2-[[4-[3-(ethylamino)-2-pyridinyl]-1-piperzinyl]methyl]-3,4- dihydro-2,5,7,8-tetramethyl-, (Z)-2-buten dioate (U78518F), on human breast cancer cells are described. U74500A inhibited cell proliferation in a dose-dependent manner with IC50 values of approximately 1.7 and 1.2 microM when cells were exposed to the drug for 3 and 5 days, respectively. The non-steroid antioxidants, alpha-tocopherol and nordihydroguaiaretic acid, showed weak or no activity at the same dose range. All three lazaroids inhibited, dose dependently, the proliferation of mouse lymphocytes but only at IC50 values ranging between 20-30 microM. The specificity of action was studied by including other steroids: progesterone, testosterone and hydrocortisone. Both sex hormones stimulated cell proliferation at low (less than 10(-5) M) concentrations but inhibited at higher doses with IC50 values of 26 (progesterone) and 80 (testosterone) microM. Hydrocortisone (IC50 0.17 microM), on the other hand, inhibited cell proliferation by 70% over a wide range of doses. Human breast cancer cells appear to have a greater sensitivity than the mouse lymphocytes to lazaroids. The antiproliferative effects of lazaroids in cancer cells may be, at least in part, due to an interaction with glucocorticoid receptors.
Kim
R S
RS
Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine Winnipeg, Canada.
Zaborniak
C L
CL
Begleiter
A
A
LaBella
F S
FS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology*; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011281:Pregnatrienes / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D005021:Ethylamines; D010879:Piperazines; D011281:Pregnatrienes; D011725:Pyridines; C074965:U 74389F; C072017:U 78518F; D014810:Vitamin E; D013739:Testosterone; D011374:Progesterone; D009637:Masoprocol; C053356:U 74500A