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

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 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.

Dichotomy in Hedgehog Signaling between Human Healthy Vessel and Atherosclerotic Plaques

“…Thereafter, proteins were resolved on molecular size using SDS polyacrylamide gel electrophoresis and analyzed by Western blot essentially as described previously (19). Briefly, membranes were blocked in 1% fat-free dried milk or bovine serum albumin (2%) in Tris-buffered saline (TBS)/0.1% Tween 20 (TBST) and incubated overnight at 4°C with the appropriate primary antibody.…”

The Medicinal Value of Biodiversity: New Hits to Fight Cancer

“…A more recent epigenetic role for parthenolide in cancer has been shown, by specifically inhibiting DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) activities, leading to DNA hypomethylation in vitro and in vivo (Liu et al, 2009;Ghantous et al, 2010). Also, the ability of plant secondary metabolites, such as vitamins, isothiocyanates, quercetin, catechins, resveratrol, epigallocatechin-3-gallate (EGCG), genistein and curcumin, to prevent and/or inhibit tumor growth, either alone or in combination with other anticancer drugs and/or other phytochemicals has been documented (de Souza et al, 2005;de Souza et al, 2006;Hemalswarya & Doble, 2006;de Souza Queiroz et al, 2007;Newman & Cragg, 2007;de Fátima et al, 2008a;Bailly, 2009;Camargo et al, 2011). In this respect, all-trans-retinoic acid (vitamin A) is now widely used for the treatment of myeloid leukemia (Sanz & Lo-Coco, 2011) and vitamin D is in clinical trial for this disease (Trump et al, 2006).…”

“…In this respect, all-trans-retinoic acid (vitamin A) is now widely used for the treatment of myeloid leukemia (Sanz & Lo-Coco, 2011) and vitamin D is in clinical trial for this disease (Trump et al, 2006). Recently, we provided evidence that photoderivatives of riboflavin, a constituent of the vitamin B complex (vitamin B2), possess strong activity in hematological malignancy as well (de Souza et al, 2006). The molecular mechanism involved the activation of caspase 8 induced by overexpression of Fas and FasL and mitochondrial amplification mechanisms associated with the stimulation of ceramide production by sphingomyelinase and ceramide synthase.…”

“…The molecular mechanism involved the activation of caspase 8 induced by overexpression of Fas and FasL and mitochondrial amplification mechanisms associated with the stimulation of ceramide production by sphingomyelinase and ceramide synthase. In addition, activation of this cascade led to an inhibition of mitogen activated protein kinases cJun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK and survival mediators [Protein kinase B (PKB/Akt) and inhibitor of apoptosis protein 1 (IAP1)], upregulation of pro-apoptotic Bax and downregulation of cell cycle progression regulators (de Souza et al, 2006). The potential of such vitamin-derived products in solid tumors was also demonstrated in androgen-independent human prostate cancer (PC3) cells (de Souza Queiroz et al, 2007).…”

Epigenetic Regulation of Human Riboflavin Transporter 2(hRFT2) in Cervical Cancers from Uighur Women

“…Riboflavin also participates in various metabolic redox reactions, and is involved in one carbon metabolism, which is a network of interrelated biochemical pathways that generate one carbon groups needed for physiologic processes (De Souza et al, 2006). Disruption of one carbon metabolism can interfere with DNA replication, DNA repair, and regulation of gene expression through methylation, each of which could promote carcinogenesis (Kim, 2004).…”