title: Induction of the differentiation of HL-60 promyelocytic leukemia cells by nonsteroidal anti-inflammatory agents in combination with low levels of vitamin D3.
abstract: Previous experiments have shown that a variety of agents that interfere with the activity of the transcription factor NF-kB significantly enhanced the differentiation of HL-60 leukemia cells when combined with low levels of the monocytic/macrophagic differentiating agent vitamin D3. These include an antisense phosphorothioate oligonucleotide to the Rel A subunit of NF-kB, vitamin E and other antioxidants, and curcumin. Acetylsalicylic acid and other nonsteroidal anti-inflammatory agents represent another group of agents that have been reported to inhibit NF-kB at serum levels approximating those obtained during long-term therapy of chronic inflammatory states. To determine whether nonsteroidal anti-inflammatory agents also were capable of enhancing the differentiation of HL-60 leukemia cells produced by vitamin D3, we measured the effects of a variety of nonsteroidal anti-inflammatory agents on the maturation of HL-60 cells produced by low levels of vitamin D3. Acetylsalicylic acid by itself had no significant effect on the differentiation of HL-60 cells; however, this agent markedly increased the degree of differentiation produced by low levels of vitamin D3. Furthermore, a variety of other nonsteroidal anti-inflammatory agents of different chemical classes exhibited similar enhancements of the maturation of HL-60 cells when combined with vitamin D3. An analogous increase in the differentiation of HL-60 cells was also obtained by combination of several nonsteroidal anti-inflammatory agents with the granulocytic inducing agent, retinoic acid, but not with dimethylsulfoxide. The nonsteroidal anti-inflammatory agents also enhanced the differentiation of HL-60 cells when combined with vitamin D analogs which share the receptor binding properties of vitamin D3; however, a vitamin D analog which caused significant calcium mobilization, but was less effective in receptor binding than vitamin D3, did not induce the differentiation of HL-60 cells in the presence or absence of anti-inflammatory agents. The findings suggest that the nonsteroidal anti-inflammatory agents may have utility in the treatment of acute promyelocytic leukemia when used with the D vitamins or retinoic acid.
authors.affiliation: Department of Pharmacology, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sokoloski
authors.forename: A C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D004347:Drug Interactions; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002762:Cholecalciferol; D001241:Aspirin