Silibinin can induce differentiation as well as enhance vitamin D 3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors

Jing Zhang, Jonathan S. Harrison, Milan Uskokovic, Michael Danilenko, George P. Studzinski

    Research output: Contribution to journalArticlepeer-review

    27 Scopus citations

    Abstract

    Induction of terminal differentiation is a conceptually attractive approach for the therapy of neoplastic diseases. Although vitamin D derivatives (deltanoids) can induce differentiation of AML cells in vitro, so far deltanoids have not been successfully brought to the clinic, due to the likelihood of life-threatening hypercalcemia. Here, we incubated freshly obtained blood cells from patients with AML with a plant antioxidant (PAOx), silibinin (SIL), alone or together with a deltanoid. Twenty patients with AML (all subtypes except M3) were available for this study, and in 14 (70%), SIL (60 μM) either induced differentiation ex vivo, or enhanced differentiation induced by deltanoids, or both. Interestingly, SIL acting alone induced differentiation only in cases in which chromosome aberrations could not be detected. In eleven samples sufficient material was available for a limited analysis of the underlying events. Quantitative RT-PCR showed that differentiation markers were upregulated at the mRNA level by both SIL and deltanoids, suggesting that intracellular signaling pathways upstream of transcription factors (TFs) were activated by these agents. Western analysis for proteins which function as TFs in deltanoid-induced monocytic differentiation, such as members of Jun and C/EBP families, surprisingly demonstrated that SIL upregulated all these TFs in the cases tested. This suggests that although the presence of SIL may not always be sufficient to induce differentiation, it can serve as a differentiation enabling factor for blasts obtained from a large proportion of patients with AML. Thus, SIL/deltanoid combinations warrant further consideration as preventive/ therapeutic regimens in human leukaemia.

    Original languageEnglish
    Pages (from-to)124-132
    Number of pages9
    JournalHematological Oncology
    Volume28
    Issue number3
    DOIs
    StatePublished - 1 Jan 2010

    Keywords

    • Acute myeloid leukaemia
    • C/EBP
    • Differentiation
    • Silibinin
    • c-Jun

    ASJC Scopus subject areas

    • Hematology
    • Oncology
    • Cancer Research

    Fingerprint

    Dive into the research topics of 'Silibinin can induce differentiation as well as enhance vitamin D 3-induced differentiation of human AML cells ex vivo and regulates the levels of differentiation-related transcription factors'. Together they form a unique fingerprint.

    Cite this