Opioid Growth Factor Research Articles

Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that primarily affects women during the second or third decade of life. The mechanism is hypothesized to involve unregulated peripheral inflammation resulting in blood-brain barrier damage, and eventual axonal damage and demyelination. Based on this understanding, the animal model of MS, experimental autoimmune encephalomyelitis (EAE), often is utilized to study lymphocyte activation. Therapeutic paradigms of exogenous opioid growth factor (OGF) or low-dose naltrexone (LDN) treatment can modulate EAE, but little is reported regarding OGF or LDN effects on peripheral inflammation, microglia activation, and/or macrophage proliferation. Moreover, little is known about differential responses to LDN or OGF relative to the duration and timing of treatment. Utilizing a female mouse model of EAE, two treatment regimens were established to investigate differences between prophylactic treatment and traditional therapy initiated at the time of disease presentation. Prophylactic OGF or LDN treatment delayed the onset of behavior, suppressed neutrophil replication, and curtailed lymphocyte proliferation which ultimately improved behavioral outcome. Traditional therapy with OGF or LDN reversed behavioral deficits, restored OGF and IL-17 serum levels, and inhibited microglial activation within 8days. Reduced serum OGF levels in untreated EAE mice correlated with increased microglia activation within lumbar spinal cords. Both treatment regimens of OGF or LDN reduced activated microglia, whereas only prophylactic treatment prevented CNS macrophage aggregation. These data demonstrate that the timing of LDN or OGF treatment initiation alters outcomes and can prevent or reverse behavioral deficits, cytokine activation, and spinal cord pathology.

Dysregulation of the OGF-OGFr pathway and associated diabetic complications.

Diabetes is a worldwide epidemic with more than 550 million individuals expected to be diagnosed with the disease by 2030. Complications associated with diabetes affect nearly all systems, but more than 54% of diabetic individuals have ocular surface disorders including keratopathy, dry eye or altered corneal surface sensitivity, and nearly 70% experience slow healing foot ulcers which if left untreated, can lead to amputation. There is new information regarding the underlying pathophysiology associated with these complications, as well as potential treatment. This commentary assembles data on preclinical studies showing that corneal surface complications such as dry eye and sensitivity, as well as delayed epithelial wound healing in the cornea and skin in diabetic rats and mice, correlate with a dysregulation of the opioid growth factor (OGF)-opioid growth factor receptor (OGFr) regulatory axis. The peptide in this pathway, OGF, chemically termed [Met5]-enkephalin, is elevated in the serum of humans and animals with either type 1 or type 2 diabetes. The cause for this finding is unknown. However, there are studies that demonstrate that blockade of the interactions between OGF (or elevated levels of OGF) and its receptor can reverse and, in some cases, prevent the onset of diabetic corneal complications. Clinicians and healthcare workers need to recognize this fundamental pathophysiology leading to diabetic complications. Dysfunction of the OGF-OGFr growth regulatory system plays a role in the development of ocular surface complications and delayed cutaneous wound healing complications in multiple animal models of both Type 1 and Type 2 diabetes. Modulation of this system may hold promise for reversing or even preventing these diabetic complications in humans. Moreover, monitoring serum levels of OGF should be investigated as an indicator of the development of these and other diabetic complications.

A 20-Year Research Trend Analysis of the Influence of Anesthesia on Tumor Prognosis Using Bibliometric Methods

BackgroundBibliometric analysis is used to gain a systematic understanding of developments in the field of the influence of anesthesia on tumor prognosis and changes in research hot spots over the past 20 years.MethodsRelevant publications from the Web of Science Core Collection (WoSCC) were downloaded on May 5, 2021. Acquired data were then analyzed using the Online Analysis Platform of Literature Metrology (http://biblimetric.com) and the CiteSpace software was used to analyze and predict trends and hot spots in this field.Results1,521 publications on the influence of anesthesia on tumor prognosis were identified and 1494 qualifying records were included in the final analysis. The leading country in this field was the United States of America (USA). The University of Texas MD Anderson Cancer Center (Houston, TX, USA) and Pennsylvania State University (State College, PA, USA) featured the highest number of publications among all institutions. Co-citation cluster labels revealed characteristics of ten main clusters: total intravenous anesthesia, opioid growth factor receptor, gastric cancer cell, opioid receptor, murine model, natural killer cell activity, health-related quality, glioma cell, opioid switching and mu-type opioid receptor. Keyword burst detection indicated that randomized controlled trials (RCTs), volatile anesthetics, and ropivacaine were the newly emerging research hot spots.ConclusionsThis study compiled 1494 publications covering anesthesia and tumor prognosis research and showed that the direction of these studies is likely in transition from opioids and their receptors to other anesthetics, and from retrospective studies to prospective randomized controlled trials. It provides guidance for further research and clinical applications on choosing anesthetic methods and drugs.

A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment

This study examined the antitumor effect of methionine enkephalin (MENK) against lung cancer in vivo and in vitro and explored the underlying mechanisms. Changes in the immune status of the tumor microenvironment (TME) in response to MENK administration were examined in mice. MENK significantly inhibited the proliferation of lung cancer cells in vivo and in vitro by regulating the Wnt/β-catenin pathway and causing cell cycle arrest at the G0/G1 phase. Knockdown of opioid growth factor receptor abolished the effect of MENK on lung cancer cells. The immune status of the TME of mice differed between the MENK and control groups. MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Immunohistochemical analysis of the expression of cytokines in the TME showed that MENK upregulated IL-15, IL-21, IFN-γ, and granzyme B and downregulated IL-10 and TGF-β1 in mice. Taken together, these finding indicate that MENK may be a potential agent for lung cancer treatment in the future, especially for overcoming immune escape and immune resistance.

Regulatory role of methionine enkephalin in myeloid-derived suppressor cells and macrophages in human cutaneous squamous cell carcinoma

The antitumor effects of methionine enkephalin (MENK), also known as opioid growth factor (OGF), including its inhibitory effects on cutaneous squamous cell carcinoma (CSCC), have been established. In this study, we determined the precise mechanism by which MENK suppresses CSCC cell growth. In particular, MENK induced G0/G1 cell cycle arrest and promoted apoptosis in CSCC cells via the Bcl-2/Bax/Caspase-3 signaling pathway. Moreover, MENK reduced immunosuppression by downregulating the number of myeloid-derived suppressor cells (MDSCs) and regulating the polarization of tumor-associated macrophages from M2 to M1 in vivo. Furthermore, JAK2/STAT3, an important tumor-promotion and immunosuppression signaling pathway that is involved in MDSC expansion in tumors and macrophage polarization, was inhibited. These findings highlight the potential of the JAK2/STAT3 signaling pathway as a therapeutic target and suggest the clinical application of MENK for CSCC.

Low Doses Naltrexone: The Potential Benefit Effects for its Use in Patients with Cancer.

Naltrexone (NTX) is an opioid antagonist that inhibits cell proliferation in vivo when administered in low doses. Naltrexone in low doses can reduce tumor growth by interfering with cell signalling as well as by modifying the immune system. It acts as an Opioid Growth Factor receptor (OGFr) antagonist and the OGF-OGFr axis is an inhibitory biological pathway present in human cancer cells and tissues, being a target for the treatment with naltrexone low-dose (LDN). Clinical trials have proposed a unique mechanism(s) allowing LDN to affect tumors. LDN shows promising results for people with primary cancer of the bladder, breast, liver, lung, lymph nodes, colon and rectum. This short review provides further evidence to support the role of LDN as an anticancer agent.

Naltrexone blockade of OGFr enhances cutaneous wound closure in diabetic rats

AimsNon-healing wounds are a major complication for the 27 million individuals in the United States with diagnosed diabetes. This study investigated the efficacy of a novel formulation to treat diabetic foot ulcers by targeting an underlying pathophysiology of diabetes. Main methodsThe proprietary GMP formulations utilized increasing dosages of naltrexone (NTX) to block the inhibitory peptide Opioid Growth Factor (OGF) from binding to the OGF receptor (OGFr). Efficacy of topical application was studied using male Sprague-Dawley rats with uncontrolled (T1D) or insulin-controlled (T1D-INS) diabetes. Wound closure time, tensile strength of healed skin, and angiogenesis were endpoints. Serum drug dispersion was assessed. Key findingsResidual wound areas were significantly reduced within 2 days of surgery in T1D rats receiving either 0.5% or 1% NTX. By day 10, NTX-treated wounds were 5-fold smaller than those measured on T1D rats receiving vehicle. Tensile strength measurements and morphology studies revealed that NTX treatment of cutaneous wounds on T1D or T1D-INS rats accelerated epithelialization, accelerated angiogenesis, and increased the integrity of healed skin. Topical application of NTX resulted in no visible toxicity, and the NTX was not detected in serum. SignificanceProprietary GMP formulations up to 1% NTX were found to be effective and safe for topical treatment of full-thickness cutaneous wounds in diabetic rats. The mechanism of action involves blockade of the OGF-OGFr axis, a pathway known to become dysregulated with diabetes. These data warrant proof-of-concept human clinical trials for treatment of diabetic foot ulcers.

Methionine enkephalin activates autophagy and stimulates tumour cell immunogenicity in human cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is a common skin tumour. Due to weak immunogenicity, recurrence is frequent after treatment. In this study, we explored the effects and mechanisms of methionine enkephalin (MENK), an endogenous opioid peptide and negative growth regulator, in CSCC. MENK inhibited A431 cell proliferation and promoted apoptosis through the opioid growth factor receptor (OGFr). Importantly, MENK also induced autophagy in CSCC and stimulated the emission of DAMPs in A431 cells, which resulted in enhanced activation of dendritic cells (DC).In conclusion, MENK provides an effective method with therapeutic potential to modulate the CSCC microenvironment by utilizing autophagy in the cancer cells.

Ocular surface complications result from dysregulation of the OGF-OGFr signaling pathway in female diabetic rats.

Approximately 4.5 million women in the United States exhibit diabetes-associated ocular complications. The time course and magnitude of these complications, and their association with the dysregulation of the opioid growth factor (OGF)-OGF receptor (OGFr) signaling pathway are unknown. The present study investigated the onset and magnitude of ocular surface complications and the association with a dysregulated OGF-OGFr signaling pathway in diabetic female rats. Adult female Sprague-Dawley rats were injected with streptozotocin in order to establish a model of type 1 diabetes (T1D), and a subset received insulin (T1D-INS). Blood glucose, body weight, tear production and corneal sensitivity, as well as serum and tissue expression levels of OGF and OGFr, were assessed. Corneal epithelial wound healing was also evaluated. In a second study, female T1D rats were treated with topical naltrexone (NTX) to determine whether blockade of the OGF-OGFr signaling pathway by NTX altered development of corneal surface complications. Female T1D rats had elevated glucose levels and reduced body weight compared with control and T1D-INS rats. In both diabetic groups, tear production was decreased within 2 weeks and corneal sensitivity was decreased 2.5-fold within 5 weeks, while corneal epithelial wound healing was delayed only in T1D rats. Serum and tissue levels of OGF and OGFr were elevated in diabetes. Twice daily NTX treatment reversed most ocular surface complications in the diabetic female rats. The present data demonstrated a seminal discovery in female T1D rats, in which the onset and magnitude of diabetes-associated ocular surface complications were associated with dysregulation of the OGF-OGFr regulatory pathway. Blockade of the OGF-OGFr pathway with the opioid receptor antagonist NTX prevented the onset and/or decreased the magnitude of these deficits. The current data support the need for translational research on this therapeutic approach for diabetic human subjects.

Thebaine Derivatives as a New Regulator of Tumor Angiogenesis

Cancer pain management is mostly done by opioids; however, they have further pharmacological effects apart from analgesia including angiogenesis. In this study, peripherally acting ligands of µ opioid receptor (MOR) were synthesized and evaluated as a tool to investigate peripheral effects of opioids in controlling angiogenesis. For this purpose, the designed compounds were synthesized from thebaine and N-(4-dimethylaminophenyl)maleimide under Diels-Alder and nucleophilic substitution (SN) reactions with different alkyl halides to form quaternary ammonium salts. In silico study conducted by docking these compounds on active (5C1M) and inactive (4DKL) form of MOR. Results of in silico study indicate that all compounds were more likely to be an antagonist of MOR based on their interaction patterns with MOR. For biological assessment, they were tested on human umbilical vein endothelial cells using a proliferation MTT test. Also, these compounds were studied by in vivo hot plate test to examine the ability of compounds to cross the blood-brain barrier (BBB). In biological tests, these compounds showed double-faced results with pro-angiogenic effect in lower doses and anti-angiogenic effect in higher doses. Their pro-angiogenic effect was comparable with VEGF. The in vivo study proved their peripherally acting nature. The contradictory effects of opioids on angiogenesis could be explained by its two different targets including MOR and opioid growth factor receptor. This gives a privilege to opioids for use as an angiogenesis controller. By developing more peripherally acting opioids with minimizing central effects, more research in this area is hoped.

Sex differences in the magnitude of diabetic ocular surface complications: Role of serum OGF

Diabetes is associated with dysregulation of the Opioid Growth Factor (OGF) – OGF receptor (OGFr) regulatory pathway leading to elevated OGF levels in serum and tissues. This study was designed to investigate the role of sex on the magnitude of ocular surface complications by direct comparison of male and female type 1 diabetic (T1D) rats. Male and female adult Sprague-Dawley rats were rendered T1D; a cohort of T1D male and female rats received insulin (=T1D-INS). Tear production, corneal surface sensitivity, as well as serum levels of estrogen, testosterone, OGF and OGFr were measured. Multivariate analyses were performed for correlations between sex, condition and magnitude of ocular surface alterations. Significant differences were noted in all parameters tested between male and female Normal, T1D, and T1D-INS animals over the 8-week observation period. Multivariate analyses revealed that the magnitude of complications is greater in female T1D rats and has a strong negative correlation with serum estrogen and OGF. Ocular surface complications associated with T1D have an earlier onset and greater magnitude in female T1D rats than male diabetic animals, and are related to elevated levels of OGF.

β-endorphin and opioid growth factor as biomarkers of physical ability in multiple sclerosis

BackgroundMultiple sclerosis (MS) is an autoimmune-mediated degenerative disorder with increased peripheral inflammation disrupting the blood brain barrier. With increasing MS-related healthcare costs, the requirement to validate minimally invasive biomarkers has become imperative. MethodsRelapsing-remitting MS patients on disease modifying therapies were consented at the Penn State Health MS Clinic to provide blood samples for analyses of serum cytokines and endogenous opioid peptides, as well as to complete the MSQOL-54 survey. ResultsSerum OGF levels in MS patients on glatiramer acetate (mean = 326 pg/ml), dimethyl fumarate (mean = 193.3 pg/ml) and natalizumab (mean = 393.4 pg/ml) were significantly elevated (p < 0.01) compared to healthy controls (mean = 98.46 pg/ml). Individuals with elevated OGF levels also had increased levels of TNFα (r = 0.78) and IL-17A (r = 0.81). Only patients treated with glatiramer acetate had significant (p < 0.01) elevations in serum β-endorphin levels. Analyses of MS-QoL 54 data showed no significant differences in physical or mental composite scores between treatment groups. However, serum levels of β-endorphin had a direct correlation with physical health composite score (r = 0.70) in all treatments. Serum vitamin D levels had an indirect relationship with 25-foot walk test times (r = 0.47). ConclusionBoth regression and cohort data suggest that serum levels of OGF, β-endorphin, and vitamin D are potential biomarkers for physical disease status in MS.

Approaches to the Development of a Low-dose Naltrexone Preparation in the Form of a Nasal Spray (Review)

Introduction . Naltrexone hydrochloride belongs to µ-opioid receptor antagonists and is widely used in the treatment of alcohol and drug addiction at an oral dose of 50 mg/day. It is also a blocker of other receptors – opioid growth factor and Toll-like factor, which is especially evident at doses of 1.5–5 mg/day. This allows it to be used to treat diseases associated with impaired immunity. Text . To date, there is a significant amount of data indicating the effectiveness of naltrexone hydrochloride administered orally in doses from 1.5 to 5.0 mg per day for the treatment of significant diseases such as AIDS, cancer, autism, multiple sclerosis, etc. However, on the pharmaceutical market still lacks a drug that provides such doses. Due to the fact that oral administration of naltrexone is associated with its first-pass hepatic metabolism and the formation of significant amounts of substances that cause side effects of neuropsychiatric effects and gastrointestinal disorders, as well as the possible effect of naltrexone and its metabolites by other drugs, which in large amounts are used for these diseases, the creation of a parenteral dosage form is relevant. Conclusion . The review presents current research in the field of low-dose naltrexone application, its mechanisms of action, and considers possible areas of application in medical practice. The disadvantages of oral administration are noted and an alternative route of administration such as intranasal is considered. Approaches to the development of a finished dosage form – nasal spray, are implemented when selecting the optimal content of the active substance and auxiliary components of the drug. The most promising is the creation of a drug based on thermoreversible polymers with a naltrexone hydrochloride content of up to 3,0 %.

Detection of opioid growth factor in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a recent prevalent central nervous system disease that affects the brain and spinal cord. It is assumed that it is an intermediate immune disorder in the central nervous system and is complex with incomplete etiology. Some research have confirmed that the Opioid growth factor(OGF), which was called chemically Enkephalin [Met5], is considered as a biomarker for the onset of MS. The purpose of this study was to look into the biomarker level of OGF and its correlation with body mass index(BMI) among patients with MS. A total number of 100 patients were diagnosed in two groups (54 early diagnosis of MS without treatment, 46 early diagnosis with treatment) according to McDonald criteria and 50 healthy control groups were included. All demographic data of the study samples were recorded (age, gender), as well as clinical data such as (BMI),and level OGF(serum and saliva) estimated by ELISA method. The current study revealed that the mean+SD of serum OGF in patients with multiple sclerosis for both groups(947.167 ± 134.262 ng/ml) was less concentrated than the control group (1046.642 ± 63.605 ng/ml) with a very large difference (P &lt;0.01). While the mean concentration of OGF in saliva was (960.158 ± 91.684 ng/ml) for patients with multiple sclerosis (early diagnosis group without treatment and the treatment group), its concentration was higher than the control group (880.059 ± 87.700 ng/ml) with a large statistical significance (P &lt;0.01). The current study showed an important correlation between the body mass index and serum OGF level at (p = 0.022) in the early diagnosis group for multiple sclerosis patients with treatment, , while in the early diagnosis group for multiple sclerosis patients without treatment, a very significant association was found between BMI and serum OGF level at (p = 0.009). Interestingly, the current study showed that saliva biomarker (OGF) would be a good predictor for diagnosing MS.

Blockade of OGFr delays the onset and reduces the severity of diabetic ocular surface complications.

The opioid growth factor (OGF)-OGF receptor (OGFr) pathway is present in the ocular surface and functions to maintain homeostasis of the epithelium. The OGF-OGFr pathway has been reported to be dysregulated in diabetic individuals and animal models, and is reflected in elevations of the inhibitory growth factor, OGF, chemically termed [Met5]-enkephalin. Recently, our laboratory reported elevated levels of OGF and OGFr in the serum and corneal epithelium of type 1 diabetic rats, suggesting that dysregulation of the OGF-OGFr axis may lead to dry eye, abnormal corneal surface sensitivity, and delayed re-epithelialization. Blockade of OGF-OGFr pathway using naltrexone, a potent opioid receptor antagonist, reverses dry eye symptoms and restores corneal surface sensitivity in diabetic rats when used as a therapy. Based on the evidence that both OGF and OGFr are elevated in type 1 diabetic rats, this study examined whether systemic or topical naltrexone treatment initiated at the time of induction of hyperglycemia could protect against the development of diabetic ocular surface complications. Diabetic male Sprague-Dawley rats treated systemically or topically with naltrexone had a delayed onset of dry eye and altered corneal surface sensitivity, and an improved healing rate for corneal wounds, that were comparable to non-diabetic rats. Serum levels of OGF were normal for rats receiving systemic naltrexone, and OGF tissue levels were normal for type 1 diabetic rats receiving twice daily naltrexone drops. OGFr levels remained elevated. These data support the role of the OGF-OGFr axis in regulation of ocular surface complications, and suggest that naltrexone therapy may be beneficial for pre-diabetic and early diabetic individuals.

Met5]-enkephalin preserves diffusion metrics in EAE mice

Multiple sclerosis is a chronic progressive neurological disorder that has few distinctive biomarkers associated with disease progression or response to therapy. This research investigated whether non-invasive imaging correlated with animal behavior and morphological indicators of disease in response to serum levels of [Met5]-enkephalin. Using the experimental autoimmune encephalomyelitis (EAE) model, adult female C57BL/6 J mice were randomized to receive daily injections of 0.1 mg/kg naltrexone (NTX) (= low dose naltrexone, LDN), 10 mg/kg Opioid Growth Factor (OGF) (chemically termed [Met5]-enkephalin) or saline beginning at the time of disease induction. Daily composite behavior scores were recorded over a 30-day period based on tail tone, gait, righting reflex, and limb strength. Prior to disease onset (day 7), and at peak disease (day 18), mice were imaged and tissues (blood and spinal cord) collected at day 30 for serum analyses of OGF and morphology. Serum OGF levels of EAE mice treated with saline were significantly reduced from baseline and from normal mice. Longitudinal cohort data demonstrated an increase in fractional anisotropy in all cohorts by day 18. There was a significant decrease in radial diffusivity in the saline group seen at day 18 whereas the axial diffusivity was not altered amongst treatment groups. Treatment with OGF or LDN resulted in mean diffusivity rates that were comparable to baseline (normal) levels at days 7 and 18. Luxol fast blue staining of the lumbar spinal cords demonstrated a 16 % reduction in myelin staining in saline treated EAE animals when compared to OGF and LDN treated EAE mice. Immunohistochemistry with Olig2 (pan-oligodendrocyte marker) and myelin basic protein (MBP) revealed that OGF and LDN treatment restored the area (%) of MBP and number of oligodendrocytes to that of normal spinal cord (∼75 %). Saline treated EAE mice had more demyelination and fewer oligodendrocytes than normal mice. Collectively, these data suggest that a panel of biomarkers including imaging, serum biomarker levels, and behavior correlate with progression of disease, and may begin to validate use of specific non-invasive markers for MS.

Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.

The Role of Opioids and Their Receptors in Urological Malignancy: A Review.

We reviewed the literature surrounding the role of opioids and their receptors in urological malignancy. Recent studies have suggested clinically significant effects of agonism or antagonism of opioid receptors on cancer related outcomes and tumorigenesis. The focus of these efforts has centered on nonurological malignancies. However, a compelling body of evidence is growing in the fields of prostate, bladder and kidney cancer. A systematic review of English language articles published through 2020 was conducted with key phrases related to kidney, bladder or prostate cancer, and opioids or narcotics. A total of 837 unique records were identified, of which 49 were selected for full text review and 33 were included in the qualitative analysis. Eight records were identified via citation review and 1 study was recently presented at a national meeting. Retrospective reviews suggest poorer disease specific and recurrence-free survival with increased perioperative opioid administration in patients undergoing prostate or bladder cancer surgery. However, the data are controversial. Kappa opioid receptors are implicated in both proliferation and inhibition of prostate cancer cell growth across in vitro studies, with a proposed interaction with the androgen cascade. Similarly opioid growth factor receptor is highly expressed in prostate cancer cells and repressed by androgens. Prostate cancer tissue stains more intensely for the mu opioid receptor, and patients with higher expression have poorer oncologic outcomes. Opioid agonism in vitro induces urothelial cell carcinoma proliferation, migration and invasion, with possible additional influence from interactions with the bradykinin b2 receptor. Agonism of the mu, kappa and delta opioid receptors induces renal cell carcinoma tumorigenesis, possibly via upregulation of survivin. Meanwhile, opioid growth factor receptor agonism has the opposite effect in renal cell carcinoma. Evidence surrounding the role of opioids and their receptors in urological malignancy is provocative and should serve as an impetus for further investigation.

Low-dose naltrexone inhibits colorectal cancer progression and promotes apoptosis by increasing M1-type macrophages and activating the Bax/Bcl-2/caspase-3/PARP pathway

The incidence of colorectal cancer (CRC) is increasing annually worldwide. However, traditional chemotherapy has obvious side effects. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Therefore, the aim of this study was to explore the mechanisms underlying the inhibitory effect of LDN on CRC progression in vivo and in vitro. We found that expression of macrophage markers (F4/80, CD68) was increased in nude mice treated with LDN compared with the control group (p < 0.05). Additionally, levels of M1 macrophage phenotypic markers (CD80) and cytokines (tumor necrosis factor-α, TNF-α) were higher than in the control group (p < 0.05). LDN was able to upregulate expression of the opioid growth factor receptor (OGFr) and apoptosis-related factors Bax, caspase-9, caspase-3, and PARP and downregulate expression of Bcl-2, Survivin, and Ki67 to promote tumor cell apoptosis. Therefore, we speculate that LDN reduces tumor size by increasing levels of M1-like macrophages and activating the Bax/Bcl-2/caspase-3/PARP signaling pathway to induce apoptosis. We suggest that LDN has potential for the treatment of CRC.

Opioid Growth Factor and its Derivatives as Potential Non-toxic Multifunctional Anticancer and Analgesic Compounds.

Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer, its morbidity and mortality are still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of the new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidates for the development of novel, non-toxic, and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.