Dezocine, An Opioid Analgesic, Exerts Antitumor Effects in Triple-Negative Breast Cancer by Targeting Nicotinamide Phosphoribosyltransferase

Xue, Chenyang; Chen, Wei; Yuan, Aiwu; Chen, Cheng; Li, Shuaihu; Chen, Kai; Zhao, Yang; Xiao, Tian; Shao, Genze; Zou, Yongdong; Zheng, Duo

doi:10.3389/fphar.2021.600296

Cited by 12 publications

(7 citation statements)

References 36 publications

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“… 61–63 , 70 However, in vitro studies have found that dezocine directly inhibits the viability and migration of HepG2 and Hep 3B HCC cells in a concentration-dependent manner by inhibiting cellular oxyglycolysis and its malignant potential through the serine/threonine kinase 1 (Akt1)-glycogen synthase kinase 3 (GSK-3) pathway, 71 and they have found that dezocine exerts an antitumor effect by targeting nicotinamide phosphoribosyltransferase in triple-negative breast cancer. 72 Thus, these findings suggest that dezocine has direct antitumor effects in vitro. However, the mechanism and significance are still unknown.…”

Section: Dezocine Has Potential To Regulate the Clinical And Biologic...mentioning

confidence: 78%

Dezocine Has the Potential to Regulate the Clinical and Biological Features of Tumors

Hu¹,

Liu²,

Qiu³

et al. 2022

DDDT

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Cancer is the second leading cause of death following ischemic heart disease in the world and the primary clinical, social and economic burden. Surgical resection is the main measure for the treatment of the vast majority of solid tumors. However, the recurrence and metastasis of tumors occur at different periods after surgery in many cases undergoing radical tumor surgery, which is the main cause of death of tumor patients. Moreover, tumor patients are prone to suffer from mental depression, which may increase the morbidity and mortality of tumors. Tumors have a series of clinical biological signs with the following five main features: postoperative pain and cancerous pain; suppression of antitumor immunity; angiogenesis in tumors; proliferation, growth and metastasis of tumors; and mental depression. Surgery is the first treatment in the majority of cancer patients with solid tumors. Opioids are required for anesthesia and postoperative analgesia. For cancerous pain control, patients undergo surgery, and their quality of life of is improved. However, traditional opioids, such as morphine, may inhibit antitumor immunity, induce vascular growth of tumors and promote the proliferation, invasion and migration of cancer cells, and traditional opioids can induce a risk of somatic dependence. However, studies have found that not all opioids share the effects of immunosuppression, tumor proliferation promotion and angiogenesis induction. Dezocine, a novel opioid with specific pharmacological mechanisms, has been demonstrated to regulate the five clinical and biological features of tumors. We reviewed the preclinical and clinical studies of dezocine on postoperative pain and cancer pain in tumor patients as well as the immune system, tumor angiogenesis, tumor proliferation, tumor growth, tumor metastasis and mental depression. We proposed that dezocine may be the best choice of opioids for anesthesia and analgesia in cancer patients.

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Section: Dezocine Has Potential To Regulate the Clinical And Biologic...mentioning

confidence: 78%

Dezocine Has the Potential to Regulate the Clinical and Biological Features of Tumors

Hu¹,

Liu²,

Qiu³

et al. 2022

DDDT

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“…Studies have shown that NAMPT is overexpressed in colorectal cancer, gastric cancer, and glioma and is used as an anticancer target [15][16][17][18][19]; however, it has not become a widespread target in AML treatment, mainly due to the genetic heterogeneity of AML. Therefore, the selection of AML with high sensitivity to the NAMPT inhibitor has become a key premise for choosing NAMPT as a therapeutic target for leukemia.…”

Section: Resultsmentioning

confidence: 99%

NAM-NAD+-ADO metabolic reprogramming is a key factor for DNMT3A mutation to promote leukemia development through regulating cell cycle and immune microenvironment

Wang

Yang²,

Wang³

et al. 2022

Preprint

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DNMT3A-R882H mutation is a frequent epigenetic mutation in acute myeloid leukemia (AML)-M4 and M5, participating in the regulation of cell growth and differentiation by blocking the binding of transcription factor complexes to DNA. However, effective approaches that directly target this inactivating mutation for therapy remain lacking. For the first time, we show that the DNMT3A-R882H mutation can switch leukemia cells to undergo nicotinamide (NAM) and nicotinamide adenine dinucleotide (NAD+) metabolism and influence the formation of cyclin-CDK complexes by affecting the deacetylation function of SIRT6. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) can reduce the NAD + required for SIRT6 function, degrade CDKN1A/CDKN1B, and effectively induce cell cycle arrest and apoptosis. The NAMPT inhibitor FK866 can optimize the immune-infiltrating microenvironment by reducing the production of the downstream metabolite adenosine (ADO). Animal experiments have shown that NAMPT inhibition or knockdown can significantly inhibit tumor cell growth, reduce spleen infiltration of tumor cells, and prolong mouse lifespan. Our findings provide a potential direction for a targeted therapy at the metabolic level in AML with DNMT3A mutations.

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“…This could help to solve the current problem of the opioid crisis. Also, dezocine is finding use for cancer pain management in China due to its analgesic properties [5] as well as its potential tumor inhibition properties [15,16]. Dezocine has potential therapeutic value for neuropathic pain, without evidence of tolerance or dependence, as demonstrated in a rodent model of neuropathic pain [6].…”

Section: Discussionmentioning

confidence: 99%

Dezocine is a Biased Ligand without Significant Beta-Arrestin Activation of the mu Opioid Receptor

Grothusen¹,

Lin²,

Jin³

et al. 2022

Transl Perioper & Pain Med

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Dezocine is an opioid that was used in clinical practice for acute pain management in the US (1986US ( to 2011 and is currently in use in China. It is not listed as a controlled substance in the US due to no reported cases of addiction. Dezocine is a partial agonist at the mu opioid receptor (MOR); however, it is unclear whether dezocine can activate both the G protein pathway and the beta-arrestin pathway. In this study we hypothesized that dezocine does not activate the beta-arrestin pathway, which could be the potential molecular mechanism by which dezocine is not addictive or at least less addictive than other classic opioids. Both morphine, a MOR full agonist and buprenorphine, a partial MOR agonist similar to dezocine, were used for comparison purposes. The major side effects of dezocine in clinical usage are its gastrointestinal side effects and first pass effects; therefore, we explored the possibility of administering dezocine intranasally in rodents to demonstrate the feasibility of intranasal administration for new clinical usage purposes. With proper formulation it is possible to administer dezocine intranasally to achieve a high concentration in the brain in the rodent model. The results indicate that dezocine does not activate the betaarrestin pathway in MOR. Intranasal delivery of dezocine achieves a much higher medication concentration in the blood and brain as compared to intraperitoneal injection. It also persists a longer time before it falls below detection in the blood. This study provides a possible explanation of why dezocine is not addictive or at least less addictive than other commonly used opioids. This study also demonstrates that intranasal administration offers an alternative strategy for its potential clinical applications. MethodsAll the chemicals used in this study were commercially obtained and were either analytical or pharmaceutical grade with more than 98% purity. Nanodezocine (dezocine complexed with 2-hydroxypropylγ-cyclodextrin) is a patented formulation produced in our laboratory [9]. HTLA cells, an HEK293 cell line stably expressing a tTA-dependent luciferase reporter and a beta-arrestin-TEV fusion gene, were kindly provided by the laboratory of Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill [10]. The animal protocols were approved by the Institutional

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Dezocine, An Opioid Analgesic, Exerts Antitumor Effects in Triple-Negative Breast Cancer by Targeting Nicotinamide Phosphoribosyltransferase

Cited by 12 publications

References 36 publications

Dezocine Has the Potential to Regulate the Clinical and Biological Features of Tumors

Dezocine Has the Potential to Regulate the Clinical and Biological Features of Tumors

NAM-NAD+-ADO metabolic reprogramming is a key factor for DNMT3A mutation to promote leukemia development through regulating cell cycle and immune microenvironment

Dezocine is a Biased Ligand without Significant Beta-Arrestin Activation of the mu Opioid Receptor

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