A promising action of riboflavin as a mediator of leukaemia cell death

A.C. De Souza, L. Kodach, F.R. Gadelha, C.L. Bos, A.D.M. Cavagis, H. Aoyama, Maikel Peppelenbosch, C.V. Ferreira

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    Abstract

    Besides having a pivotal biological function as a component of coenzymes, riboflavin appears a promissing antitumoral agent, but the underlying molecular mechanism remains unclear. In this work, we demonstrate that irradiated riboflavin, when applied at mu M concentrations, induces an orderly sequence of signaling events finally leading to leukemia cell death. The molecular mechanism involved is dependent on the activation of caspase 8 caused by overexpression of Fas and FasL and also on mitochondrial amplification mechanisms, involving the stimulation of ceramide production by sphingomyelinase and ceramide synthase. The activation of this cascade led to an inhibition of mitogen activated protein kinases: JNK, MEK and ERK and survival mediators (PKB and IAP1), upregulation of the proapoptotic Bcl2 member Bax and downregulation of cell cycle progression regulators. Importantly, induction of apoptosis by irradiated riboflavin was leukaemia cell specific, as normal human lymphocytes did not respond to the compound with cell death. Our data indicate that riboflavin selectively activates Fas cascade and also constitutes a death receptor-engaged drug without harmful side effects in normal cells, bolstering the case for using this compound as a novel avenue for combating cancerous disease.

    Original languageEnglish
    Pages (from-to)1761-1771
    Number of pages11
    JournalApoptosis
    Volume11
    Issue number10
    DOIs
    Publication statusPublished - Oct-2006

    Keywords

    • riboflavin
    • photosensitizer
    • apoptosis
    • myeloid leukaemic cells
    • signal transduction
    • PROTEIN-TYROSINE PHOSPHATASES
    • AQUEOUS-SOLUTION
    • INDUCED DIFFERENTIATION
    • BIOLOGICAL FUNCTIONS
    • VISIBLE-LIGHT
    • HL60 CELLS
    • APOPTOSIS
    • CERAMIDE
    • EXPRESSION
    • FAS

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