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

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 microM concentrations, induces an orderly sequ...

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Bibliographic Details
Published in:Apoptosis (London) 2006-10, Vol.11 (10), p.1761-1771
Main Authors: de Souza, Ana Carolina Santos, Kodach, Liudmila, Gadelha, Fernanda R, Bos, Carina L, Cavagis, Alexandre D Martins, Aoyama, Hiroshi, Peppelenbosch, Maikel P, Ferreira, Carmen Veríssima
Format: Article
Language:English
Subjects:
Apoptosis
Cell cycle
Cell Death - drug effects
Cell Survival - drug effects
HL-60 Cells
Humans
Kinases
Leukemia
Leukemia - drug therapy
Leukemia - metabolism
Leukemia - pathology
Light
Lymphocytes
Mitogen-Activated Protein Kinases - metabolism
Models, Biological
Mortality
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Riboflavin - pharmacology
Riboflavin - radiation effects
Riboflavin - therapeutic use
Side effects
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Summary: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 microM 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.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-006-9549-2