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

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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 μM 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.

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Abbreviations

ERK:

extracellular signal-regulated kinase

Fas (CD95):

Fas receptor

FasL (CD95L):

Fas ligand

HL60:

human myeloid leukemia cell line

IAP1:

inhibitory apoptosis protein type 1

JNK:

c-jun-NH2-terminal protein kinase

MAPK:

mitogen-activated protein kinase

MEK:

MAPK/ERK kinase

PCNA:

proliferating cell nuclear antigen

PKB:

protein kinase B

PP2A:

phosphoprotein phosphatase 2A

RF:

riboflavin

STAT:

signal transducer and activator of transcription

TNF:

tumor necrosis factor

TNFR:

tumor necrosis factor receptor

TRAF:

receptor-associated factor.

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Authors and Affiliations

  1. Department of Biochemistry, State University of Campinas, Brazil

    Ana Carolina Santos de Souza, Fernanda R. Gadelha, Alexandre D. Martins Cavagis, Hiroshi Aoyama & Carmen Veríssima Ferreira

  2. Laboratory of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, NL-1105, AZ Amsterdam, The Netherlands

    Liudmila Kodach & Carina L. Bos

  3. Department of Cell Biology, University Medical Center Groningen, A. Deusinglaan 1, NL-9713 AV, Groningen, The Netherlands

    Maikel P. Peppelenbosch

Authors
  1. Ana Carolina Santos de Souza
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  2. Liudmila Kodach
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  3. Fernanda R. Gadelha
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  4. Carina L. Bos
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  5. Alexandre D. Martins Cavagis
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  6. Hiroshi Aoyama
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  7. Maikel P. Peppelenbosch
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  8. Carmen Veríssima Ferreira
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Correspondence to Carmen Veríssima Ferreira.

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de Souza, A.C.S., Kodach, L., Gadelha, F.R. et al. A promising action of riboflavin as a mediator of leukaemia cell death. Apoptosis 11, 1761–1771 (2006). https://doi.org/10.1007/s10495-006-9549-2

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