B lymphocyte proliferation is suppressed by the opioid growth factor–opioid growth factor receptor axis: Implication for the treatment of autoimmune diseases

The opioid growth factor–opioid growth factor receptor axis: Homeostatic regulator of cell proliferation and its implications for health and disease

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.

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

Endogenous opiates and behavior: 2010.

Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis

BACKGROUND: Advanced pancreatic cancer carries the poorest prognosis of all gastrointestinal malignancies. Once the tumor has spread beyond the margins of the pancreas, chemotherapy is the major treatment modality offered to patients; however, chemotherapy does not significantly improve survival. OBJECTIVE: Opioid growth factor (OGF; [Met(5)]-enkephalin) is a natural peptide that has been shown to inhibit growth of pancreatic cancer in cell culture and in nude mice. The purpose of this study was to evaluate the effects of OGF biotherapy on subjects with advanced pancreatic cancer who failed chemotherapy. METHODS: In a prospective phase II open-labeled clinical trial, 24 subjects who failed standard chemotherapy for advanced pancreatic cancer were treated weekly with OGF 250 µg/kg intravenously. Outcomes measured included clinical benefit, tumor response by radiographic imaging, quality of life, and survival. RESULTS: Clinical benefit response was experienced by 53% of OGF-treated patients compared to historical controls of 23.8% and 4.8% for gemcitabine and 5-fluorouracil (5-FU), respectively. Of the subjects surviving more than eight weeks, 62% showed either a decrease or stabilization in tumor size by computed tomography. The median survival time for OGF-treated patients was three times that of untreated patients (65.5 versus 21 days, p < 0.001). No adverse effects on hematologic or chemistry parameters were noted, and quality of life surveys suggested improvement with OGF. LIMITATIONS: Measurements other than survival were not allowed in control patients, and clinical benefit comparisons were made to historical controls. CONCLUSION: OGF biotherapy improves the clinical benefit and prolongs survival in patients with pancreatic cancer by stabilizing disease or slowing progression. The effects of OGF did not adversely alter patient quality of life. The use of OGF biotherapy at earlier stages of disease or in combination with other chemotherapeutic agents may further improve the outcome of this malignancy.

https://www.dovepress.com/getfile.php?fileID=5967

Harold H Harvey

Papers

Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer.