Proposed mechanism of action of morphine in MMP-9 regulation. Morphine affects MMP-9 production via different signalling pathways by which activation of each of these pathways depends on experimental conditions such as doses of morphine and administration modes. Chronic treatment or a high dose of morphine leads to adenylyl cyclase (AC) activation, resulting in cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP responsive element-binding (CREB) cascade activation and consequently inhibition of NF-κB and MMP-9 production. Acute or low dose treatment of morphine, however, causes opioid receptor activation following G beta-gamma (Gβγ) complex release and phosphoinositide 3-kinase (PI3K)/ protein kinase B (PKB) signalling activation, resulting in nuclear factor kappa B (NF-κB) activation and hence MMP-9 production. Additionally, morphine can induce constitutive nitric oxide synthase (cNOS) and nitric oxide (NO) production in different cancerous and non-cancerous cells including non-small-cell lung carcinoma, endothelial cells, neurons and macrophages via the μ3 opiate receptor. The NO induction further supresses the NF-κB action which in turn may inhibit MMP-9 production

Proposed mechanism of action of morphine in MMP-9 regulation. Morphine affects MMP-9 production via different signalling pathways by which activation of each of these pathways depends on experimental conditions such as doses of morphine and administration modes. Chronic treatment or a high dose of morphine leads to adenylyl cyclase (AC) activation, resulting in cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP responsive element-binding (CREB) cascade activation and consequently inhibition of NF-κB and MMP-9 production. Acute or low dose treatment of morphine, however, causes opioid receptor activation following G beta-gamma (Gβγ) complex release and phosphoinositide 3-kinase (PI3K)/ protein kinase B (PKB) signalling activation, resulting in nuclear factor kappa B (NF-κB) activation and hence MMP-9 production. Additionally, morphine can induce constitutive nitric oxide synthase (cNOS) and nitric oxide (NO) production in different cancerous and non-cancerous cells including non-small-cell lung carcinoma, endothelial cells, neurons and macrophages via the μ3 opiate receptor. The NO induction further supresses the NF-κB action which in turn may inhibit MMP-9 production

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Opioids are widely administered to alleviate pain, including chronic pain in advanced cancer patients. Among opioids, morphine is one of the most clinically effective drugs for the palliative management of severe pain. In the last few decades, there has been a debate around the possible influence of opioids such as morphine on tumour growth and met...

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... Other complex molecular interactions may occur when drugs are administered. In cancer setting, opioids may modulate MMP-9 production and then cancer progression [109]. Morphine may determine this action through an independent opioid receptor, but the cell type is dependent on the mechanism. ...
... There are three main metabolic pathways in this process. Morphine chronic or high-dose use may activate adenylate cyclase and then cyclic adenosine monophosphate (cAMP), resulting in protein kinase A (PKA)/cAMP-responsive element-binding activation, and finally the inhibited production of the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and MMP-9 [109]. Acute or low doses can stimulate the opioid receptor, activating the Gβγ complex which, at the end of the chain, determines NF-κB activation and MMP-9 increases. ...
... Acute or low doses can stimulate the opioid receptor, activating the Gβγ complex which, at the end of the chain, determines NF-κB activation and MMP-9 increases. The third additional mechanism is the increase in nitric oxide, resulting in NF-κB inhibition and MMP-9 decreases [109]. ...
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Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes associated with extracellular matrix protein turnover and tissue degradation. They participate to many different physiological reactions but are also hyperactivated in several diseases. Various literature studies have documented that MMPs play a role in the modulation of neuropathic and nociceptive pain. The heterogeneity of clinical and pre-clinical data is an important issue in this experimental context. Despite the presence of a good number of studies on MMP inhibitors, these drugs showed scarce efficacy and relevant side effects. In the present manuscript, we reviewed studies in the literature that define a possible role of MMPs in pain and the effects of their modulation.
... Thus, direct cytotoxic effects of local and systemic anesthetic agents such as lidocaine, ropivacaine, and propofol have been described suggesting anticancer effects (5,6). However, morphine reportedly activates matrix metalloproteinases that then would promote the dissemination of tumors (7). Moreover, perioperative immunomodulatory factors such as undernutrition, anemia, neoadjuvant chemotherapy, as well as the concomitant use of mechanistically distinct anesthetic agents during oncosurgery, render the translation of partially promising preclinical results into clinical practice difficult. ...
... Until now, opioids have been the most commonly used analgesics for controlling acute pain. However, preclinical data indicate that opioids mediate pro-tumorigenic effects via the activation of matrix metalloproteinases and oncogenes like c-Myc as well as via an increase in DNA methylation (52)(53)(54). Of note, DNA methylation leads to the expression of the mu opioid receptor and predicts the response to endogenous endorphins and opioid analgesics (55). ...
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Defective silencing of tumor suppressor genes through epigenetic alterations contributes to oncogenesis by perturbing cell cycle regulation, DNA repair or cell death mechanisms. Reversal of such epigenetic changes including DNA hypermethylation provides a promising anticancer strategy. Until now, the nucleoside derivatives 5-azacytidine and decitabine are the sole DNA methyltransferase (DNMT) inhibitors approved by the FDA for the treatment of specific hematological cancers. Nevertheless, due to their nucleoside structure, these inhibitors directly incorporate into DNA, which leads to severe side effects and compromises genomic stability. Much emphasis has been placed on the development of less toxic epigenetic modifiers. Recently, several preclinical studies demonstrated the potent epigenetic effects of local anesthetics, which are routinely used during primary tumor resection to relief surgical pain. These non-nucleoside molecules inhibit DNMT activity, affect the expression of micro-RNAs and repress histone acetylation, thus exerting cytotoxic effects on malignant cells. The in-depth mechanistic comprehension of these epigenetic effects might promote the use of local anesthetics as anticancer drugs.
... [20][21][22] In this context, it would not be surprising that surgical interventions with their components of mental, nutritional, mechanic and inflammatory distress as well as the associated polypharmacy (including the administration of antibiotics, benzodiazepines, nonsteroidal anti-inflammatory drugs, general and local anesthetics, vasoactive amines, glucocorticoids…) would affect anticancer immunosurveillance, as suggested by statistically significant epidemiological associations. [23][24][25][26][27][28][29][30][31][32][33][34] Here, we investigated the possible impact of several local anesthetics that are currently used in the clinics on cancer immunosurveillance in preclinical models. For this, we determined the effects of six local anesthetics on immunogenic cancer cell stress pathways and determined their possible antineoplastic effects by injecting them into established tumors. ...
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Background: Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice. Results: In vitro, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane. In vivo, locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics. Conclusion: Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
... Matrix metalloproteinase 2 (MMP-2) and MMP-9 production can be time-and concentrationdependently inhibited by morphine in breast cancer cells [72]. MMPs participate in matrix degradation, embryogenesis, angiogenesis, wound healing, and tumor progression, promoting tissue remodeling [66,73,74]. Compared with the control group using normal saline (NS), mice injected intraperitoneally with morphine had reduced MMP-9 concentrations and inhibited TIMP-1 and TIMP-3/4, reducing the invasion and chemotactic potential of endothelial cells [75], which was consistent with the research of Afsharimani [76]. ...
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Purpose of Review Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid receptors (MOR) on tumor progression and providing new ideas for targeting the MOR in cancer treatment. Recent Findings Studies estimated that opioids facilitate tumor progression and are related to the worse prognosis in cancer patients. As the primary receptor of opioids, MOR is involved in the regulation of malignant transformation of tumors and participating in proliferation, invasion, metastasis, and angiogenesis. Summary MOR may be a new molecular marker of malignant tumors and thus become a new target for cancer therapy, which may be beneficial to the outcomes of cancer patients.
... Similarly, morphine precondition was found to prevent the deleterious effects of LPS on microglia cells (Gwak et al., 2010). Previous data could be explained by a mu Y. L. Chen et al., 2006;Eisenstein, 2019;Franchi et al., 2012;Khabbazi et al., 2019;P. Zhang et al., 2020). ...
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Inflammatory pathway and disruption in glutamate homeostasis join at the level of the glia, resulting in various neurological disorders. In vitro studies have provided evidence that membrane proteins connexions (Cxs) are involved in glutamate release, meanwhile, excitatory amino‐acid transporters (EAATs) are crucial for glutamate reuptake (clearance). Moreover, pannexin‐1 (Panx‐1) activation is more detrimental to neurons. Their expression patterns during inflammation and the impacts of IκB kinase (IKK) inhibition, morphine, and galantamine on the inflammatory‐associated glutamate imbalance remain elusive. To investigate this, rats were injected with saline or lipopolysaccharide. Thereafter, vehicles, morphine, galantamine, and BAY‐117082 were administered in different groups of animals. Subsequently, electroencephalography, enzyme‐linked immunosorbent assay, western blot, and histopathological examinations were carried out and various indicators of inflammation and glutamate level were determined. Parallel analysis of Cxs, Panx‐1, and EAAts in the brain was performed. Our findings strengthen the concept that unregulated expressions of Cxs, Panx‐1, and EAATs contribute to glutamate accumulation and neuronal cell loss. Nuclear factor‐kB (NF‐κB) pathway can significantly contribute to glutamate homeostasis via modulating Cxs, Panx‐1, and EAATs expressions. BAY‐117082, via inhibition of IkK, promoted the anti‐inflammatory effects of morphine as well as galantamine. We concluded that NF‐κB is an important component of reshaping the expressions of Cxs, panx‐1, and EAATs and the development of glutamate‐induced neuronal degeneration.
... Therefore, these MMPs expression levels effectively reflect the aggressiveness of cancer cells and are related to poor prognosis in various cancers [25,26]. MMP9 is a critical member of MMP family which plays a key role in degrading basement membrane and has been proved to enhance tumor invasion and metastasis in many different types of cancer [27,28]. Some studies also reported that the invasive and metastatic abilities of breast cancer cells were reduced by inhibition of MMP9 [13,29]. ...
Article
Natriuretic peptide receptor A (NPRA), one of the natriuretic peptide receptors, plays important roles in circulatory system. Recently some studies showed that NPRA was involved in tumorigenesis, however, its role in the development of breast cancer remains unclear. In this study, we observed that NPRA expression was upregulated in breast cancer tissues and NPRA high expression was associated with poor clinicopathological features. In addition, we found that patients with high NPRA expression had a worse 5-year survival and NPRA was an independent factor for predicting the prognosis of breast cancer patients. Knocking down NPRA expression reduced the proliferation, migration and invasion of breast cancer cells. Overexpressing NPRA was able to enhance the malignant behaviors of breast cancer cells. Furthermore, NPRA promoted the invasive phenotype through upregulating matrix metalloproteinase-9 (MMP9). Mechanistically, NPRA increased MMP9 expression through activating STAT3. We identified that NPRA might serve as a prognostic marker and p-STAT3 and MMP9 could be a potential target of NPRA in breast cancer patients.
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Opioids have been used for medicinal purposes as an analgesic and recreational purposes as a euphorigenic throughout human history. Cancer patients are often treated with different doses of opioids concurrently with anti-cancer drugs for pain relief without exhibiting excessive adverse effects. The intersection of the biology of pain, opioid therapy, and disease progression represents the crux of the matters and is of potentially great importance in cancer care. For more than 20 years, multiple investigations have focused on the stimulatory effects of opioids on cancer cell growth, while in-depth studies on the inhibitory effects on cancer cell growth development have usually been neglected. This paper reviews the evidence regarding opioid therapies and their anti-cancer effects on various malignancies. Likewise, we have a glimpse into the molecular mechanisms necessary for pinpointing their positive or negative impacts on malignancies to raise awareness and stimulate more excellent dialogue regarding their carcinogenic/anticarcinogenic roles.
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Angiogenesis plays a vital role in tumor progression and metastasis. To better understand the role of anesthesia in tumor biology, we previously reported that bupivacaine displayed the inhibitory effects in endothelial cells. In this work, we demonstrated that fentanyl, an opioid medication commonly used in cancer patients, stimulated tumor angiogenesis. We found that fentanyl at nanomolar concentrations significantly stimulated capillary network formation of human lung tumor-associated endothelial cell (HLT-EC) in a similar manner as vascular endothelial growth factor (VEGF), and furthermore that the stimulatory effect of fentanyl was mainly involved in early stage of HLT-EC vascular structure assembly. Particularly, fentanyl significantly increased HLT-EC growth and migration. Fentanyl also protected HLT-EC from apoptosis induced by growth factor withdrawal. In contrast, the same concentrations of fentanyl did not affect human lung cancer cell growth and survival. Fentanyl stimulated migration of some but not all tested human lung cancer cells. Mechanism analysis suggested that fentanyl activates multiple pro-angiogenic signaling pathways, including VEGFR2/FAK/PI3K/Akt and small GTPases. Our work systematically demonstrates that fentanyl stimulates tumor angiogenesis via activating multiple pro-angiogenic signaling pathways. Our findings highlight the potential adverse effect of fentanyl in cancer patients.