title: Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.
abstract: Naltrexone (NTX) is an opioid antagonist that inhibits or accelerates cell proliferation in vivo when utilized in a low (LDN) or high (HDN) dose, respectively. The mechanism of opioid antagonist action on growth is not well understood. We established a tissue culture model of LDN and HDN using short-term and continuous opioid receptor blockade, respectively, in human ovarian cancer cells, and found that the duration of opioid receptor blockade determines cell proliferative response. The alteration of growth by NTX also was detected in cells representative of pancreatic, colorectal and squamous cell carcinomas. The opioid growth factor (OGF; [Met(5)]-enkephalin) and its receptor (OGFr) were responsible for mediating the action of NTX on cell proliferation. NTX upregulated OGF and OGFr at the translational but not at the transcriptional level. The mechanism of inhibition by short-term NTX required p16 and/or p21 cyclin-dependent inhibitory kinases, but was not dependent on cell survival (necrosis, apoptosis). Sequential administration of short-term NTX and OGF had a greater inhibitory effect on cell proliferation than either agent alone. Given the parallels between short-term NTX in vitro and LDN in vivo, we now demonstrate at the molecular level that the OGF-OGFr axis is a common pathway that is essential for the regulation of cell proliferation by NTX.
authors.affiliation: Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Donahue
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: McLaughlin
authors.forename: Ian S
authors.initials: IS
authors.lastname: Zagon
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004745:Enkephalins / Q000096:biosynthesis; D006801:Humans; D009271:Naltrexone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011498:Protein Precursors / Q000096:biosynthesis; D011957:Receptors, Opioid / Q000096:biosynthesis / Q000187:drug effects* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D004745:Enkephalins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D011957:Receptors, Opioid; C033593:methionine-enkephalin receptor; D009271:Naltrexone; C033660:preproenkephalin