Low-dose naltrexone targets the opioid growth factor–opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model

2011 ◽  
Vol 236 (9) ◽  
pp. 1036-1050 ◽  
Author(s):  
Renee N Donahue ◽  
Patricia J McLaughlin ◽  
Ian S Zagon
Keyword(s):  
Cell Proliferation ◽  
Tissue Culture ◽  
Growth Factor ◽  
Low Dose ◽  
Growth Factor Receptor ◽  
Opioid Growth Factor ◽  
Culture Model ◽  
Tissue Culture Model ◽  
Low Dose Naltrexone ◽  
Inhibit Cell Proliferation

scholarly journals Regulation of Tenon's Capsule Fibroblast Cell Proliferation by the Opioid Growth Factor and the Opioid Growth Factor Receptor Axis

2010 ◽  
Vol 51 (10) ◽  
pp. 5054 ◽  
Author(s):  
Matthew S. Klocek ◽  
Joseph W. Sassani ◽  
Renee N. Donahue ◽  
Patricia J. McLaughlin ◽  
Ian S. Zagon
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Fibroblast Cell ◽  
Opioid Growth Factor ◽  
Tenon’S Capsule ◽  
Tenon's Capsule

scholarly journals Featured Article: Modulation of the OGF–OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis

2018 ◽  
Vol 243 (4) ◽  
pp. 361-369 ◽  
Author(s):  
Michael D Ludwig ◽  
Ian S Zagon ◽  
Patricia J McLaughlin
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokine ◽  
Low Dose ◽  
Serum Levels ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Low Dose Naltrexone ◽  
Experimental Autoimmune

The endogenous neuropeptide opioid growth factor, chemically termed [Met5]-enkephalin, has growth inhibitory and immunomodulatory properties. Opioid growth factor is distributed widely throughout most tissues, is autocrine and paracrine produced, and interacts at the nuclear-associated receptor, OGFr. Serum levels of opioid growth factor are decreased in patients with multiple sclerosis and in animals with experimental autoimmune encephalomyelitis suggesting that the OGF-OGFr pathway becomes dysregulated in this disease. This study begins to assess other cytokines that are altered following opioid growth factor or low-dose naltrexone modulation of the OGF-OGFr axis in mice with experimental autoimmune encephalomyelitis using serum samples collected in mice treated for 10 or 20 days and assayed by a multiplex cytokine assay for inflammatory markers. Cytokines of interest were validated in mice at six days following immunization for experimental autoimmune encephalomyelitis. In addition, selected cytokines were validated with serum from MS patients treated with low-dose naltrexone alone or low-dose naltrexone in combination with glatiramer acetate (Copaxone®). Experimental autoimmune encephalomyelitis mice had elevated levels of 7 of 10 cytokines. Treatment with opioid growth factor or low-dose naltrexone resulted in elevated expression levels of the IL-6 cytokine, and significantly reduced IL-10 values, relative to saline-treated experimental autoimmune encephalomyelitis mice. TNF-γ values were increased in experimental autoimmune encephalomyelitis mice relative to normal, but were not altered by opioid growth factor or low-dose naltrexone. IFN-γ levels were reduced in opioid growth factor- or low-dose naltrexone-treated experimental autoimmune encephalomyelitis mice relative to saline-treated mice at 10 days, and elevated relative to normal values at 20 days. Validation studies revealed that within six days of immunization, opioid growth factor or low-dose naltrexone modulated IL-6 and IL-10 cytokine expression. Validation in human serum revealed markedly reduced IL-6 cytokine levels in MS patients taking low-dose naltrexone relative to standard care. In summary, modulation of the OGF-OGFr pathway regulates some inflammatory cytokines, and together with opioid growth factor serum levels, may begin to form a panel of valid biomarkers to monitor progression of multiple sclerosis and response to therapy. Impact statement Modulation of the opioid growth factor (OGF)–OGF receptor (OGFr) alters inflammatory cytokine expression in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Multiplex cytokine assays demonstrated that mice with chronic EAE and treated with either OGF or low-dose naltrexone (LDN) had decreased expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and the anti-inflammatory cytokine IL-10 within 10 days or treatment, as well as increased serum expression of the pro-inflammatory cytokine IL-6, relative to immunized mice receiving saline. Multiplex data were validated using ELISA kits and serum from MS patients treated with LDN and revealed decreased in IL-6 levels in patients taking LDN relative to standard care alone. These data, along with serum levels of OGF, begin to formulate a selective biomarker profile for MS that is easily measured and effective at monitoring disease progression and response to therapy.

Dependence on Nuclear Localization Signals of the Opioid Growth Factor Receptor in the Regulation of Cell Proliferation

2009 ◽  
Vol 234 (5) ◽  
pp. 532-541 ◽  
Author(s):  
Fan Cheng ◽  
Patricia J. McLaughlin ◽  
Michael F. Verderame ◽  
Ian S. Zagon
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Nuclear Localization ◽  
Fluorescent Protein ◽  
Growth Factor Receptor ◽  
Full Length ◽  
Nuclear Pore ◽  
Nucleocytoplasmic Trafficking ◽  
Nuclear Localization Signals ◽  
Opioid Growth Factor

The opioid growth factor receptor (OGFr) mediates the inhibitory action of OGF on cell replication of normal and neoplastic cells. The spatiotemporal course of OGFr nucleocytoplasmic trafficking was determined with a probe of full-length OGFr fused to enhanced green fluorescent protein (eGFP). Translation of OGFr required 8.5 hours, and transit into the nucleus required 8 hours; OGFr remained in the nucleus for 8 days. OGFr was initially expressed on the outer nuclear envelope, transited to the paranuclear cytoplasm, and into the nucleus. Transport through the nuclear pore was elucidated by mutation of the nuclear localization signal (NLS) sequences in full-length OGFr. Mutation of each NLS reduced nuclear localization by 5%–50%, whereas simultaneous mutation of NLS383–386 and NLS456–460 abolished OGFr-eGFP nuclear localization in 80% of the cells. To determine whether intact NLSs are important for the inhibition of cell proliferation, DNA synthesis was monitored with BrdU. Wild-type OGFr-eGFP–transfected cells had 20% BrdU-positive cells, whereas cells with simultaneous mutation of all three NLS sites had a 70% labeling index. These results indicate that the regulation of cell proliferation by the OGF-OGFr axis is dependent on nucleocytoplasmic translocation and reliant on the integrity of two NLSs in OGFr to interact with transport receptors.

scholarly journals The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer

2010 ◽  
Vol 298 (2) ◽  
pp. R459-R466 ◽  
Author(s):  
Diego M. Avella ◽  
Eric T. Kimchi ◽  
Renee N. Donahue ◽  
Hephzibah Rani S. Tagaram ◽  
Patricia J. McLaughlin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Hepatocellular Cancer ◽  
Cell Number ◽  
Treatment Modalities ◽  
Opioid Growth Factor ◽  
Inhibition Of Dna Synthesis ◽  
Relationship Of

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with a mortality rate approximating its incidence. Understanding the biology of these tumors, as well as treatment modalities, has been challenging. The opioid growth factor (OGF; [Met5]-enkephalin) and the OGF receptor (OGFr) form an endogenous growth-regulating pathway in homeostasis and neoplasia. In this investigation, we examined the relationship of the OGF-OGFr axis in HCC and define its presence, function, and mechanism. Using SK-HEP-1, Hep G2, and Hep 3B human HCC cell lines, we found that OGF and OGFr were present and functional. Exogenous OGF was observed to have a dose-dependent, reversible, and receptor-mediated inhibitory action on cell proliferation. Endogenous OGF was found to be constitutively produced and tonically active on cell replicative activities, with neutralization of this peptide accelerating cell proliferation. Silencing of OGFr using siRNA stimulated cell replication, even when exogenous OGF was added to the cultures, documenting its importance in mediating OGF activity. The mechanism of OGF-OGFr action on cell number was related to inhibition of DNA synthesis and not to apoptotic or necrotic pathways. Both OGF and OGFr were detected in surgical specimens of HCC, and no quantitative differences were recorded in peptide or receptor between pathological and normal specimens. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in HCC. The findings may provide important insight in designing treatment strategies for this deadly disease.

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