R. Koren et al., Synergistic anticancer activity of 1,25-dihydroxyvitamin D-3 and immune cytokines: the involvement of reactive oxygen species, J STEROID B, 73(3-4), 2000, pp. 105-112
Citations number
50
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
It was previously shown that 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) enh
ances the cytotoxic activity of tumor necrosis factor alpha (TNF alpha), do
xorubicin and menadione. A feature shared by these anticancer agents is the
involvement of reactive oxygen species (ROS) in their action. In this work
we found that 1,25(OH)(2)D-3 acted synergistically with interleukin 1 beta
(IL-1 beta) or interleukin 6 (IL-6) to inhibit the proliferation of MCF-7
breast cancer cells. The extent of the synergism was maximal at 1 nM, a con
centration at which 1,25(OH)(2)D-3, acting singly, only marginally reduced
the cell number. The thiol antioxidant, N-acetylcysteine (NAC) abolished th
e synergism between IL-1 beta or IL-6 and 1,25(OH)(2)D-3, but had only a sm
all protective effect when the cytokines acted alone. NAC and reduced gluta
thione (GSH) protected MCF-7 cells from cytotoxicity induced both by TNF al
pha alone and by TNF alpha and 1,25(OH)(2)D-3. A two-day exposure to TNF al
pha caused a 27.7 +/- 3.1% (mean +/- SEM) reduction in GSH content. This ef
fect increased to 46.4 +/- 5.5% by co-treatment with 1,25(OH)(2)D-3 which d
id not affect GSH levels on it own. We conclude that 1,25(OH)(2)D-3 can act
synergistically with anticancer cytokines present in the tumor milieu and
that ROS plays a mediatory role in this interaction. (C) 2000 Elsevier Scie
nce Ltd. All rights reserved.