Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway

Jing Zhang, Gary H. Posner, Michael Danilenko, George P. Studzinski

    Research output: Contribution to journalArticlepeer-review

    17 Scopus citations

    Abstract

    Low calcemic analogs of vitamin D are candidates for differentiation therapy of human myeloid leukemias. We report here that the seco-steroid synthesized to have resistance to intracellular degradation and low calcemia-inducing activity, 1alpha-hydroxymethyl-3beta-16-ene-24,24-difluoro-25-hydroxy-vitamin D3 (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB-4, and murine myeloid leukemia cells WEHI-3B D-. JKF has differentiation-inducing potency which is slightly lower than the physiologically active form of vitamin D, 1,25(OH)2vitamin D3 (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38MAP kinase, increases the differentiation efficiency of JKF to a level similar to the level observed when 1,25D is used in such combinations. We also show for the first time that SB inhibits the phosphorylation of MAPKAPK2, a downstream target of p38MAPK, but upregulates the phosphorylation of at least one of the isoforms of JNK (p46 JNK1) and of c-jun in all four human myeloid cell lines studied here. These studies indicate that the JNK1 pathway is positively associated with monocytic differentiation of several subtypes of myeloid leukemia cells arrested at different developmental stages. Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias.

    Original languageEnglish
    Pages (from-to)140-149
    Number of pages10
    JournalJournal of Steroid Biochemistry and Molecular Biology
    Volume105
    Issue number1-5
    DOIs
    StatePublished - 1 Jun 2007

    Keywords

    • ATF-2
    • Differentiation
    • JNK
    • MAPK
    • Myeloid leukemias
    • Vitamin D
    • c-jun
    • p38

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Endocrinology
    • Clinical Biochemistry
    • Cell Biology

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