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 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.
de Souza
Ana Carolina Santos
AC
Department of Biochemistry, State University of Campinas, Brazil.
Kodach
Liudmila
L
Gadelha
Fernanda R
FR
Bos
Carina L
CL
Cavagis
Alexandre D Martins
AD
Aoyama
Hiroshi
H
Peppelenbosch
Maikel P
MP
Ferreira
Carmen Veríssima
CV
D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008027:Light; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012256:Riboflavin / Q000494:pharmacology* / Q000528:radiation effects / Q000627:therapeutic use
D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D012256:Riboflavin