Synergistic anticancer activity of 1,25-dihydroxyvitamin D(3) and immune cytokines: the involvement of reactive oxygen species.
It was previously shown that 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) enhances the cytotoxic activity of tumor necrosis factor alpha (TNFalpha), doxorubicin 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-1beta) 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 concentration at which 1,25(OH)(2)D(3), acting singly, only marginally reduced the cell number. The thiol antioxidant, N-acetylcysteine (NAC) abolished the synergism between IL-1beta or IL-6 and 1,25(OH)(2)D(3), but had only a small protective effect when the cytokines acted alone. NAC and reduced glutathione (GSH) protected MCF-7 cells from cytotoxicity induced both by TNFalpha alone and by TNFalpha and 1,25(OH)(2)D(3). A two-day exposure to TNFalpha caused a 27.7+/-3.1% (mean +/- SEM) reduction in GSH content. This effect increased to 46.4+/-5.5% by co-treatment with 1, 25(OH)(2)D(3) which did 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.
Department of Physiology and Pahrmacology, The Basil and Gerald Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel. rkoren@post.tau.ac.il
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Koren
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Rocker
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Kotestiano
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Liberman
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D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol; D005978:Glutathione; D000111:Acetylcysteine