A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic or traumatic shock

Wheatley, Carmen

doi:10.1016/j.mehy.2006.01.036

Cited by 50 publications

(54 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, none of these pathways have yet been described as being modulated by the methionine cycle. Recently, a possible regulatory Cbl / NFkB mechanism has been outlined by Wheatley et al [35]. This mechanism could in turn control several cell functions such as TNFalpha and EGF production [36] and thus may be an important determinant of inflammation and of the coagulation cascade [35].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a possible regulatory Cbl / NFkB mechanism has been outlined by Wheatley et al [35]. This mechanism could in turn control several cell functions such as TNFalpha and EGF production [36] and thus may be an important determinant of inflammation and of the coagulation cascade [35]. Since NFkB was also shown to regulate mdr-1 mediated chemoresistance [37], it can be suggested that Cbl may downregulate mdr-1 gene expression by preventing NFkB activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: P-glycoprotein (Pgp), produced by multidrug resistance-1 gene (mdr-1), is a main mechanism developed by cancer cells to guard against anti-cancer drugs. Alterations of DNA methylation of the mdr-1 gene promoter are known to be linked to mdr-1 gene expression and are probably related to intracellular S-adenosyl-methionine. We here used HepG2 cells to determine the role of the methionine cycle (through the use of the Methionine-Synthase (MS) cofactor, cobalamin) on mdr-1 gene expression. Methods: Semiquantitative RT-PCR of mdr-1 gene, cellular retention of rhodamine-123, and vinblastine cytotoxicity were carried out on cells cultivated with and without cobalamin. Methylation status of the mdr-1 gene promoter was determined by methylation-specific PCR. Results: Addition of cobalamin to the cells led to an increase in MS activity, to a significant decrease in mdr-1 gene expression which is correlated to an increase in retention of the Pgp substrate Rhodamine 123. Furthermore, cobalamin potentiated cell sensitivity to vinblastine to the same range as that of the Pgp blocker verapamil and prevented methotrexate-induced up-regulation of mdr-1 gene expression. However, no modification in methylation of the mdr-1 gene promoter was observed. Conclusion: Cobalamin downregulates mdr-1 gene expression, as well as Pgp expression and function, and significantly increases cytotoxicity of vinblastine. The identification of this novel way of diminishing cellular resistance to the chemotherapeutic agent vinblastine holds promises of leading to better treatments for cancer patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Marguerite¹,

Béri-Dexheimer²,

Ortiou³

et al. 2007

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…[3] However, high levels of NO can be deleterious and can result in sepsis and septic shock, [4] leading to organ failure and even death. Importantly, administering cobalamins suppresses • NO-induced relaxation of smooth muscle, [5] • NO-induced vasodilation [6] and • NO-mediated inhibition of cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Studies on the Reaction of Nitrocobalamin with Glutathione: Kinetic Evidence for Formation of an Aquacobalamin Intermediate

et al. 2013

View full text Add to dashboard Cite

The essential but also toxic gaseous signaling molecule nitric oxide is scavenged by the reduced vitamin B12 complex cob(II)alamin. The resulting complex, nitroxylcobalamin (NO−-Cbl(III)), is rapidly oxidized to nitrocobalamin (NO2Cbl) in the presence of oxygen; however it is unlikely that nitrocobalamin is itself stable in biological systems. Kinetic studies on the reaction between NO2Cbl and the important intracellular antioxidant, glutathione (GSH), are reported. In this study, a reaction pathway is proposed in which the β-axial ligand of NO2Cbl is first substituted by water to give aquacobalamin (H2OCbl+), which then reacts further with GSH to form glutathionylcobalamin (GSCbl). Independent measurements of the four associated rate constants k1, k−1, k2, and k−2 support the proposed mechanism. These findings provide insight into the fundamental mechanism of ligand substitution reactions of cob(III)alamins with inorganic ligands at the β-axial site.

show abstract

“…Cobalamins inhibit nitric oxide (NO)-induced physiologies and pathologies (smooth muscle relaxation,1-3 vasodilation,4 NO-mediated inhibition of cell proliferation,5 NO-induced neural tube defects6) and both mammalian B 12 -dependent enzymes are inhibited by NO or NO donors 7-11. It has been suggested that in vivo Cbl directly scavenges NO to form NOCbl,5,12 and indeed, the reaction between a major intracellular form of Cbl, cob( ii )alamin, and NO to form NOCbl approaches the rate of diffusion and is thermodynamically favorable ( K ~ 1 × 10 8 M −1 , 25 °C) 13,14. The therapeutic potential of Cbls and related cobinamides for treating diseases associated with high NO levels is currently under investigation 2,6,12,15-17…”

Section: Introductionmentioning

confidence: 99%

Redetermination of the X-ray structure of nitroxylcobalamin: base-on nitroxylcobalamin exhibits a remarkably long Co–N(dimethylbenzimidazole) bond distance

et al. 2010

View full text Add to dashboard Cite

The X-ray structures of three new crystals of nitroxylcobalamin (NOCbl) have been determined. Unlike our earlier reported structure in which NOCbl was partially oxidized , the O atom of the nitroxyl ligand is located in a single position with a N=O bond distance of 1.12-1.14 Å, consistent with a double bond. The Co-N-O angle is in the 118.9-120.3 Å range. The α-axial Co-N(dimethylbenzimidazole) (Co-NB3) bond distance is a remarkable 2.32-2.35 Å in length, ~0.1 Å longer than that reported for all other cobalamin structures. The change in the Gibbs free energy for the base-on/base-off equilibrium now correlates extremely well with the Co-NB3 bond distance, as observed for other cobalamins.

show abstract

A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic or traumatic shock

Cited by 50 publications

References 103 publications

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Cobalamin Potentiates Vinblastine Cytotoxicity Through Downregulation of mdr-1 Gene Expression in HepG2 Cells

Mechanistic Studies on the Reaction of Nitrocobalamin with Glutathione: Kinetic Evidence for Formation of an Aquacobalamin Intermediate

Redetermination of the X-ray structure of nitroxylcobalamin: base-on nitroxylcobalamin exhibits a remarkably long Co–N(dimethylbenzimidazole) bond distance

Contact Info

Product

Resources

About