Duration of opioid receptor blockade determines biotherapeutic response

McLaughlin, Patricia J.; Zagon, Ian S.

doi:10.1016/j.bcp.2015.06.016

Cited by 47 publications

(38 citation statements)

References 89 publications

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“…In fact, a similar growth-inhibitory action has been reported for the antagonist naltrexone, which also exhibits a similar dose-dependent quality (1). The mechanism by which it exerts its anticancer effect has yet to be fully elucidated, but a number of reports have indicated both direct-effects on tumour as well as indirect modifications to immune function, which enhances host immunity against tumours.…”

Section: Discussionmentioning

confidence: 53%

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Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

Liu

Scott

Dennis

et al. 2016

International Journal of Oncology

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Abstract. It has been reported that lower doses of the opioid antagonist naltrexone are able to reduce tumour growth by interfering with cell signalling as well as by modifying the immune system. We have evaluated the gene expression profile of a cancer cell line after treatment with low-dose naltrexone (LDN), and assessed the effect that adapting treatment schedules with LDN may have on enhancing efficacy. LDN had a selective impact on genes involved with cell cycle regulation and immune modulation. Similarly, the pro-apoptotic genes BAD and BIK1 were increased only after LDN. Continuous treatment with LDN had little effect on growth in different cell lines; however, altering the treatment schedule to include a phase of culture in the absence of drug following an initial round of LDN treatment, resulted in enhanced cell killing. Furthermore, cells pre-treated with LDN were more sensitive to the cytotoxic effects of a number of common chemotherapy agents. For example, priming HCT116 with LDN before treatment with oxaliplatin significantly increased cell killing to 49±7.0 vs. 14±2.4% in cultures where priming was not used. Interestingly, priming with NTX before oxaliplatin resulted in just 32±1.8% cell killing. Our data support further the idea that LDN possesses anticancer activity, which can be improved by modifying the treatment schedule.

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Section: Discussionmentioning

confidence: 53%

“…A number of reports have identified a putative anticancer role for naltrexone when used at doses lower than those conventionally administered (1). In particular, it has been shown that these low doses of naltrexone (LDN) are able to suppress tumour growth.…”

Section: Introductionmentioning

confidence: 99%

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

Liu

Scott

Dennis

et al. 2016

International Journal of Oncology

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“…The mechanism of action of LDN is that low dosages of the opioid antagonist block the interfacing of endogenous peptides and their receptors for a short period of time, producing a biofeedback that upregulates the secretion of enkephalins and endorphins, as well as related receptors, thus allowing for enhanced interaction of the inhibitory peptide [Met 5 ]-enkephalin (i.e., opioid growth factor, OGF) [5][6][7][8]. LDN is recommended at dosages of 3-4.5 mg per day, with at least 24 hr between oral consumption.…”

Section: Clinically Isolated Syndrome (Cis) As Defined By the 2010 MCmentioning

confidence: 99%

Treatment of clinically isolated syndrome with low dose naltrexone

Ludwig¹,

A.P²,

I.S³

et al. 2015

Clin Case Rep Rev

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Clinically isolated syndrome (CIS) is an early sign of multiple sclerosis (MS). Despite being difficult to diagnose, the presentation of CIS is often accompanied by immunotherapy that is expensive and may have side effects. The purpose of this study was to evaluate CIS patients prescribed low dose naltrexone (LDN), an inexpensive, safe and tolerable compound that triggers endogenous enkephalin/endorphin release by the patient. LDN was prescribed to four female patients diagnosed with CIS in addition to FDA approved therapy. Retrospective chart reviews beginning in 2011 until present document that these women did not transition to clinically definite MS over a period of 4 years. Moreover, the patients reported that LDN therapy was without side effect and stabilized or improved their perceived quality of life and clinical status, including the reduction of fatigue. Thus, LDN may provide a safe and inexpensive alternative or addition to standard therapy of CIS.

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“…[13][14][15] As an opioid receptor antagonist, NTX lacks intrinsic biological activity and works by blocking interactions between an inhibitory peptide and its receptor. 20,21 The mechanism of action involves extended blockade of the OGF-OGFr regulatory pathway 22 that has been reported to be dysregulated in diabetes, leading to overexpression of the inhibitory peptide, OGF, chemically termed [Met 5 enkephalin]. OGF levels are elevated in diabetic humans and animals, leading to downregulation of cell proliferation and renewal processes in wound healing.…”

Section: Introductionmentioning

confidence: 99%

“…[23][24][25] Total opioid receptor blockade by NTX restores the proliferating homeostasis required for tissue repair. [13][14][15]22,[26][27][28][29] In this preclinical study, a comparison of effectiveness was made between the new NTX formulation (0.03%) and Regranex applied once daily for the treatment of cutaneous wounds in type 1 diabetic rats. In addition to cell replication, the appearance of mast cells as a marker of inflammation, and the expression of cytokines including vascular endothelial growth factor (VEGF), PDGF, and fibroblast growth factor (FGF) were evaluated for both therapies.…”

Section: Introductionmentioning

confidence: 99%

Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment of Diabetic Wounds

McLaughlin

Cain

Titunick

et al. 2017

Advances in Wound Care

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Objective: Diabetes affects more than 29 million individuals in the United States, resulting in healthcare costs approaching $245 billion. Approximately 15% of these individuals will develop a chronic, non-healing foot ulcer (diabetic foot ulcer [DFU]) that, if untreated, may lead to amputation. The current treatments for DFU are expensive, have significant side-effects, and often result in non-compliance. A new topical treatment is described that accelerates cutaneous wound repair and is disease modifying by targeting underlying aberrant diabetic pathways. Approach: The efficacy of naltrexone (NTX), an opioid receptor antagonist, and Regranex Ò was compared in preclinical studies using type 1 diabetic rats. Dorsal cutaneous wounds were treated topically with 0.03% NTX, Regranex, or moisturizing cream alone. Wound closure, DNA synthesis, and cytokine production were monitored. Results: Wound closure rates with topical NTX in type 1 diabetic rats were comparable to Regranex. Topical NTX accelerated DNA synthesis, as measured by BrdU incorporation, increased mast cells, and enhanced expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), a marker for angiogenesis. Regranex had little effect on DNA synthesis, mast cells, and VEGF expression relative to vehicle-treated wounds, and it only temporarily increased PDGF expression. Fibroblast growth factor expression was not altered by either treatment. Innovation: Topical application of 0.03% NTX cream accelerates diabetic wound closure. Conclusion: Blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis utilizing 0.03% NTX cream is comparable to standard care in preclinical studies, and it provides a safe, inexpensive, and effective alternative for treatment of diabetic wounds.

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Duration of opioid receptor blockade determines biotherapeutic response

Cited by 47 publications

References 89 publications

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy

Treatment of clinically isolated syndrome with low dose naltrexone

Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment of Diabetic Wounds

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