Methionine enkephalin, its role in immunoregulation and cancer therapy

Zhao, Dingliang; Plotnikoff, Nicolas P.; Griffin, Noreen; Song, Tao; Shan, Fengping

doi:10.1016/j.intimp.2016.02.015

Cited by 37 publications

(15 citation statements)

References 96 publications

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“…The presence of cancer cells in the tibiae during both the pain state and the resolved-pain state was confirmed with immunohistochemical staining of Cytokeratin 18. Endogenous opioids potentially play a very important role in cancer pain attenuation (Roques et al, 2012; Lesniak et al, 2016; Zhao et al, 2016). We administered naloxone, which is a non-selective antagonist of opioid receptors (van Dorp et al, 2007), to assess whether similar mechanisms might contribute in the present model and we are the first to show that naloxone rescued the pain phenotype.…”

Section: Discussionmentioning

confidence: 99%

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

et al. 2017

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In the majority of patients with advanced breast cancer, there is metastatic spread to bones resulting in pain. Clinically available drug treatments for alleviation of breast cancer-induced bone pain (BCIBP) often produce inadequate pain relief due to dose-limiting side-effects. A major impediment to the discovery of novel well-tolerated analgesic agents for the relief of pain due to bony metastases is the fact that most cancer-induced bone pain models in rodents relied on the systemic injection of cancer cells, causing widespread formation of cancer metastases and poor general animal health. Herein, we have established an optimized, clinically relevant Wistar Han female rat model of breast cancer induced bone pain which was characterized using behavioral assessments, radiology, histology, immunohistochemistry and pharmacological methods. In this model that is based on unilateral intra-tibial injection (ITI) of Walker 256 carcinoma cells, animals maintained good health for at least 66 days post-ITI. The temporal development of hindpaw hypersensitivity depended on the initial number of Walker 256 cells inoculated in the tibiae. Hindpaw hypersensitivity resolved after approximately 25 days, in the continued presence of bone tumors as evidenced by ex vivo histology, micro-computed tomography scans and immunohistochemical assessments of tibiae. A possible role for the endogenous opioid system as an internal factor mediating the self-resolving nature of BCIBP was identified based upon the observation that naloxone, a non-selective opioid antagonist, caused the re-emergence of hindpaw hypersensitivity. Bolus dose injections of morphine, gabapentin, amitriptyline and meloxicam all alleviated hindpaw hypersensitivity in a dose-dependent manner. This is a first systematic pharmacological profiling of this model by testing standard analgesic drugs from four important diverse classes, which are used to treat cancer induced bone pain in the clinical setting. Our refined rat model more closely mimics the pathophysiology of this condition in humans and hence is well-suited for probing the mechanisms underpinning breast cancer induced bone pain. In addition, the model may be suitable for efficacy profiling of new molecules from drug discovery programs with potential to be developed as novel agents for alleviation of intractable pain associated with disseminated breast cancer induced bony metastases.

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Section: Discussionmentioning

confidence: 99%

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

et al. 2017

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“…Collectively, we illustrated that MENK inhibited tumor involved inflammation, improved metabolic function of liver, and reduced the frequencies and weakened function of MDSCs, exerting the antitumor effects via opioid receptor‐mediated PI3K/AKT/mTOR pathway, which is unique from previous studies of immune‐mediated cancer therapy by MENK …”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory and metabolic reprogramming effects of MENK produce antitumor response in CT26 tumor-bearing mice

Tuo

Tian

et al. 2020

Journal of Leukocyte Biology

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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.

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“…Other studies have shown that MENK also plays an important role in the neuroendocrine and immune system. It exerts anti-tumour activity by binding to opioid receptors on immune cells and cancer cells, and acts as an immune booster [ 60 ]. In addition, MENK can inhibit the proliferation of human cancer cells through cyclin-dependent kinase inhibition pathways [ 61 ].…”

Section: Anti-tumour Mechanism Of Acpsmentioning

confidence: 99%

Anti-cancer peptides: classification, mechanism of action, reconstruction and modification

2020

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Anti-cancer peptides (ACPs) are a series of short peptides composed of 10–60 amino acids that can inhibit tumour cell proliferation or migration, or suppress the formation of tumour blood vessels, and are less likely to cause drug resistance. The aforementioned merits make ACPs the most promising anti-cancer candidate. However, ACPs may be degraded by proteases, or result in cytotoxicity in many cases. To overcome these drawbacks, a plethora of research has focused on reconstruction or modification of ACPs to improve their anti-cancer activity, while reducing their cytotoxicity. The modification of ACPs mainly includes main chain reconstruction and side chain modification. After summarizing the classification and mechanism of action of ACPs, this paper focuses on recent development and progress about their reconstruction and modification. The information collected here may provide some ideas for further research on ACPs, in particular their modification.

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Methionine enkephalin, its role in immunoregulation and cancer therapy

Cited by 37 publications

References 96 publications

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

Anti-inflammatory and metabolic reprogramming effects of MENK produce antitumor response in CT26 tumor-bearing mice

Anti-cancer peptides: classification, mechanism of action, reconstruction and modification

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