Targeting the opioid growth factor: Opioid growth factor receptor axis for treatment of human ovarian cancer

Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

Purpose: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that accounts for approximately 15% of the newly diagnosed cancers worldwide, and disproportionately affects younger women and women of color. Although many forms of breast cancer are successfully treated, new therapies are needed for TNBC. A novel regulatory system, the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) axis, plays a determining role in neoplasia. OGF is an endogenous peptide that binds specifically to OGFr to inhibit cell replication. As some human cancers grow, OGFr expression is diminished, thus limiting the therapeutic efficacy of OGF. The OGF-OGFr axis is present in human TNBC cell line MDA-MB-231 and OGF inhibits cell replication in a dosage-related, receptor-mediated manner. Methods: The present study investigated whether OGFr protein expression in human breast cancer cell lines grown in vitro or transplanted into nude mice, changed with the stage of proliferation or size of tumor using western blotting, semi-quantitative immunohistochemistry, and DNA synthesis techniques. Results: Comparison of log and confluent TNBC cultures revealed that OGF expression was significantly decreased in confluent cultures relative to levels in log-phase cells. Western blot analyses confirmed that OGFr was reduced in confluent TNBC and MCF-7 breast cancer cells in comparison to corresponding log-phase cells. Moreover, BrdU labeling was reduced in confluent cells. Small (1000 mm 3) TNBC tumors grown in nude mice were processed for semiquantitative measurement of OGF and OGFr. The expression of both peptide and receptor in large tumors was downregulated relative to small tumors. Conclusion: The reduced expression of the inhibitory peptide and receptor diminishes the efficacy of the OGF-OGFr axis as a biotherapy. These data suggest that the OGF-OGFr pathway is altered with cancer progression and one or more elements of this regulatory pathway may serve as biomarkers for TNBC growth.

Methionine enkephalin (MENK), an endogenous opioid peptide, has a role in nervous system, immune system, and anticancer therapy. Inflammation, metabolism and cancer are closely intertwined with each other. This study is to identify the correlation of the antitumor effects of MENK with systemic inflammation, liver metabolism, and immune cells as myeloid‐derived suppressor cells (MDSCs). We established a subcutaneous CT26 colon carcinoma model and a cyclophosphamide‐induced immunosuppressive model subjected to MENK. AML12 and MDSCs were used as in vitro models. The results showed that MENK treatment degraded tumor growth and inhibited proinflammatory cytokines both in tumor tissues and serum. The MENK‐treated tumor mice showed normalized liver function with glycolipid metabolic homeostasis. No inhibitory effect on CT26 tumor cell in vitro, but only reduced lipid synthesis in AML12 were presented by MENK. Meanwhile, MENK invigorated immune response in both two animal models by markedly suppressing MDSCs and enhancing T cells response. In vitro MENK‐treated MDSCs showed reduced glycolysis and less ROS production, which was mediated by PI3K/AKT/mTOR pathway. Opioid receptor antagonist naltrexone reversed most of the regulation. These results illustrate that MENK preventing development of colon carcinoma might be correlated with the suppression of inflammation, improving metabolism in liver as well as in MDSCs partly through opioid receptor, which brings new elements supporting the adjuvant therapy for tumor by MENK.