Nitrosylcobalamin potentiates the anti-neoplastic effects of chemotherapeutic agents via suppression of survival signaling.

Abstract

BACKGROUND:

Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated apoptosis and inhibits survival signaling in a variety of malignant cell lines. Chemotherapeutic agents often simultaneously induce an apoptotic signal and activation of NF-kappaB, which has the undesired effect of promoting cell survival. The specific aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination therapy.

METHODOLOGY:

Using anti-proliferative assays, electrophoretic mobility shift assay (EMSA), immunoblot analysis and kinase assays, we demonstrate an increase in the effectiveness of chemotherapeutic agents in combination with NO-Cbl as a result of suppressed NF-kappaB activation.

RESULTS:

Eighteen chemotherapeutic agents were tested in combination with NO-Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested. NO-Cbl pre-treatment resulted in decreased NF-kappaB DNA binding activity, inhibition of IkappaB kinase (IKK) enzymatic activity, decreased AKT activation, increased caspase-8 and PARP cleavage, and decreased cellular XIAP protein levels.

CONCLUSION:

The use of NO-Cbl to inhibit survival signaling may enhance drug efficacy by preventing concomitant activation of NF-kappaB or AKT.

• Authors: Joseph A Bauer, Joseph A Lupica, Heidi Schmidt, Bei H Morrison, Rebecca M Haney, Rhonda K Masci, Rebecca M Lee, Joseph A Didonato, Daniel J Lindner
• Journal: PloS one (PLoS One) Vol. 2 Issue 12 Pg. e1313 (Dec 12 2007) ISSN: 1932-6203 [Electronic] United States
• PMID: 18074035 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apolipoproteins
• NF-kappa B
• Nitroso Compounds
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• nitrosylcobalamin
• Proto-Oncogene Proteins c-akt
• I-kappa B Kinase
• Vitamin B 12

Topics

• Antineoplastic Agents (pharmacology)
• Apolipoproteins (physiology)
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Enzyme Activation
• Humans
• I-kappa B Kinase (metabolism)
• NF-kappa B (metabolism)
• Nitroso Compounds (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (physiology)
• Vitamin B 12 (analogs & derivatives, pharmacology)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)