Skip to content
2000
Volume 25, Issue 4
  • ISSN: 1566-5240
  • E-ISSN: 1875-5666

Abstract

Background

Morphine, a mu-opioid receptor (MOR) agonist commonly utilized in clinical settings alongside chemotherapy to manage chronic pain in cancer patients, has exhibited contradictory effects on cancer, displaying specificity toward certain cancer types and doses.

Objective

The aim of this study was to conduct a systematic assessment and comparison of the impacts of morphine on three distinct cancer models in a preclinical setting.

Methods

Viability and apoptosis assays were conducted on a panel of cancer cell lines following treatment with morphine, chemotherapy drugs alone, or their combination. Oxidative stress levels, along with the activities of superoxide dismutase and catalase, were measured. Rescue studies were also carried out using antioxidant reagents.

Results

Morphine induces resistance to conventional chemotherapeutic agents. It was observed that while morphine affected cell viability differently among ovarian cancer, anaplastic thyroid cancer, and oral squamous cell carcinoma, at concentrations that did not directly impact cancer cell viability, it significantly mitigated the inhibitory effects of chemotherapeutic agents across all tested cancer cells. This phenomenon persisted irrespective of the chemotherapeutic agent used, including cisplatin, doxorubicin, and 5-FU. It remained unaffected by adding naloxone, the MOR receptor antagonist, indicating that morphine's mechanism is independent of the μ-opioid receptor. Moreover, it was demonstrated that morphine heightened cellular reactive oxygen species (ROS) levels and suppressed the activities of superoxide dismutase and catalase. Rescue studies revealed that the addition of antioxidant reversed the protective impact of morphine on cancer cells against chemotherapy.

Conclusion

These findings hold promise in potentially guiding the clinical application of morphine for cancer patients undergoing chemotherapy.

Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240314564241129044548
2025-01-14
2025-09-01
Loading full text...

Full text loading...

References

  1. de MunterJ. DodlekN. KhmaladzeA. The role of cancer nurses in cancer-related pain management in Europe.Palliat. Care Soc. Pract.20231710.1177/26323524231216996 38106339
    [Google Scholar]
  2. Abdel ShaheedC. HayesC. MaherC.G. Opioid analgesics for nociceptive cancer pain: A comprehensive review.CA Cancer J. Clin.202310.3322/caac.21823 38108561
    [Google Scholar]
  3. PasternakGW Opioids and their receptors: Are we there yet? Neuropharmacology201476 Pt B0 019820310.1016/j.neuropharm.2013.03.03923624289
    [Google Scholar]
  4. WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents.2018Available from: https://www.who.int/publications/i/item/9789241550390
    [Google Scholar]
  5. OhT.K. JeonJ.H. LeeJ.M. Association of high-dose postoperative opioids with recurrence risk in esophageal squamous cell carcinoma: Reinterpreting ERAS protocols for long-term oncologic surgery outcomes.Dis. Esophagus201730101810.1093/dote/dox074 28859395
    [Google Scholar]
  6. ZhangJ. YaoN. TianS. Morphine stimulates migration and growth and alleviates the effects of chemo drugs via AMPK-dependent induction of epithelial–mesenchymal transition in esophageal carcinoma cells.Biol. Pharm. Bull.202043577478110.1248/bpb.b19‑00779 32378556
    [Google Scholar]
  7. MaY. RenZ. MaS. Morphine enhances renal cell carcinoma aggressiveness through promotes survivin level.Ren. Fail.201739125826410.1080/0886022X.2016.1256322 27866460
    [Google Scholar]
  8. LuH. ZhangH. WengM. Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer.J. Cell. Physiol.202123664445445410.1002/jcp.30161 33184860
    [Google Scholar]
  9. NiuD.G. PengF. ZhangW. Morphine promotes cancer stem cell properties, contributing to chemoresistance in breast cancer.Oncotarget2015663963397610.18632/oncotarget.2894 25686831
    [Google Scholar]
  10. ZhouZ. LiuT. ZhangJ. Morphine activates blast-phase chronic myeloid leukemia cells and alleviates the effects of tyrosine kinase inhibitors.Biochem. Biophys. Res. Commun.2019520356056510.1016/j.bbrc.2019.10.067 31615652
    [Google Scholar]
  11. ZhangK. HuangW. ChenW. Morphine stimulates angiogenesis through Akt/mTOR/eIF4E activation under serum deprivation or H 2 O 2 ‐induced oxidative stress condition.Clin. Exp. Pharmacol. Physiol.202047222723510.1111/1440‑1681.13191 31612523
    [Google Scholar]
  12. FengT. ZengS. DingJ. Comparative analysis of the effects of opioids in angiogenesis.BMC Anesthesiol.202121125710.1186/s12871‑021‑01475‑7 34702181
    [Google Scholar]
  13. KhabbaziS. HassanshahiM. HassanshahiA. PeymanfarY. SuY.W. XianC.J. Opioids and matrix metalloproteinases: the influence of morphine on MMP-9 production and cancer progression.Naunyn Schmiedebergs Arch. Pharmacol.2019392212313310.1007/s00210‑019‑01613‑6 30656360
    [Google Scholar]
  14. DaiH. FengJ. NanZ. Morphine may act via DDX49 to inhibit hepatocellular carcinoma cell growth.Aging (Albany NY)2021139127661277910.18632/aging.202946 33952717
    [Google Scholar]
  15. NishiwadaT. KawaraguchiY. UemuraK. KawaguchiM. Morphine inhibits cell viability and growth via suppression of vascular endothelial growth factor in human oral cancer HSC-3 cells.J. Anesth.201933340841510.1007/s00540‑019‑02645‑1 31049688
    [Google Scholar]
  16. KimJ.Y. AhnH.J. KimJ.K. KimJ. LeeS.H. ChaeH.B. Morphine suppresses lung cancer cell proliferation through the interaction with opioid growth factor receptor.Anesth. Analg.201612361429143610.1213/ANE.0000000000001293 27167686
    [Google Scholar]
  17. HaqueM.R. BarlassU. ArmstrongA. ShaikhM. BishehsariF. Novel role of the Mu-opioid receptor in pancreatic cancer: Potential link between opioid use and cancer progression.Mol. Cell. Biochem.202247751339134510.1007/s11010‑022‑04377‑5 35138511
    [Google Scholar]
  18. GambleM.C. WilliamsB.R. SinghN. Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward.Front. Syst. Neurosci.202216105908910.3389/fnsys.2022.1059089
    [Google Scholar]
  19. OlianasM.C. ConcasD. OnaliP. Agonist activity of naloxone benzoylhydrazone at recombinant and native opioid receptors.Br. J. Pharmacol.2006147436037010.1038/sj.bjp.0706601 16402046
    [Google Scholar]
  20. Rozenfeld-GranotG. TorenA. AmariglioN. MAP kinase activation by mu opioid receptor in cord blood CD34+CD38− cells.Exp. Hematol.200230547348010.1016/S0301‑472X(02)00786‑5 12031654
    [Google Scholar]
  21. DaiS. ZhangX. ZhangP. ZhengX. PangQ. Fentanyl inhibits acute myeloid leukemia differentiated cells and committed progenitors via opioid receptor‐independent suppression of Ras and STAT5 pathways.Fundam. Clin. Pharmacol.202135117418310.1111/fcp.12581 32564393
    [Google Scholar]
  22. SkrabalovaJ. DrastichovaZ. NovotnyJ. Morphine as a potential oxidative stress-causing agent.Mini Rev. Org. Chem.201310436737210.2174/1570193X113106660031 24376392
    [Google Scholar]
  23. ZahmatkeshM. KadkhodaeeM. SalarianA. SeifiB. AdeliS. Impact of opioids on oxidative status and related signaling pathways: An integrated view.J. Opioid. Manag.201713424125110.5055/jom.2017.0392 28953316
    [Google Scholar]
  24. TenórioM.C.S. GracilianoN.G. MouraF.A. OliveiraA.C.M. GoulartM.O.F. N-Acetylcysteine (NAC): Impacts on human health.Antioxidants202110696710.3390/antiox10060967 34208683
    [Google Scholar]
  25. YuvalJ.B. LeeJ. WuF. Intraoperative opioids are associated with decreased recurrence rates in colon adenocarcinoma: A retrospective observational cohort study.Br. J. Anaesth.2022129217218110.1016/j.bja.2022.04.024 35718564
    [Google Scholar]
  26. CaoL.H. LiH.T. LinW.Q. Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts.Sci. Rep.201661870610.1038/srep18706
    [Google Scholar]
  27. ScheffN.N. NilsenM.L. LiJ. The effect of opioids on the efficacy of immunotherapy in recurrent/metastatic squamous cell carcinoma of the head and neck.Oral Oncol.202314010636310.1016/j.oraloncology.2023.106363
    [Google Scholar]
  28. AggarwalV. TuliH. VarolA. Role of reactive oxygen species in cancer progression: Molecular mechanisms and recent advancements.Biomolecules201991173510.3390/biom9110735 31766246
    [Google Scholar]
  29. KimE.K. JangM. SongM.J. KimD. KimY. JangH.H. Redox-mediated mechanism of chemoresistance in cancer cells.Antioxidants201981047110.3390/antiox8100471 31658599
    [Google Scholar]
  30. YaoJ. MaC. GaoW. Fentanyl induces autophagy via activation of the ROS/MAPK pathway and reduces the sensitivity of cisplatin in lung cancer cells.Oncol. Rep.20163663363337010.3892/or.2016.5183 27779694
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240314564241129044548
Loading
/content/journals/cmm/10.2174/0115665240314564241129044548
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.


  • Article Type:
    Research Article
Keyword(s): cancer; cancer cells; chemotherapy; Morphine; oxidative stress; μ-opioid receptor
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test