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Morphine inhibits cell viability and growth via suppression of vascular endothelial growth factor in human oral cancer HSC-3 cells

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Abstract

Purpose

Although many oral cancer patients require opioids, the effects of morphine and related drugs on oral cancer progression have not been well established. Thus, we examined the effects of morphine exposure on the viability of human oral squamous carcinoma HSC-3 cells and aimed to identify the underlying mechanism.

Methods

We exposed HSC-3 cells to the various concentrations of morphine (0, 0.1, 1, 10, 100, or 1000 μmol/L) for 48 h and, subsequently, evaluated cell viability using the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and cytotoxicity using the lactate dehydrogenase (LDH) assay. To explore the effects of morphine on cell proliferation further, colony formation assay and cell cycle analysis were performed. Additionally, the intracellular expression of nuclear factor kappa B (NF-κB) was analyzed using flow cytometry, and vascular endothelial growth factor (VEGF)-A was evaluated using human VEGF assay.

Results

Morphine exposure reduced cell viability and enhanced cytotoxicity in HSC-3 cells in a concentration-dependent manner. The number of colonies in the morphine-treated groups was significantly lower than that in the control group. Consistent with these results, morphine exposure significantly reduced the concentration of VEGF in the cell culture medium in a concentration-dependent manner. However, our data show that morphine at clinical concentrations (0.1–10 μmol/L) does not affect cell cycle and apoptosis.

Conclusions

Our results suggest that in human oral cancer HSC-3 cells, morphine exposure inhibits cell viability and growth via suppression of VEGF in clinical conditions.

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References

  1. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology. 2008;109:180–7.

    Article  PubMed  Google Scholar 

  2. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105:660–4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lin L, Liu C, Tan H, Ouyang H, Zhang Y, Zeng W. Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. Br J Anaesth. 2011;106:814–22.

    Article  CAS  PubMed  Google Scholar 

  4. Lazarczyk M, Matyja E, Lipkowski AW. A comparative study of morphine stimulation and biphalin inhibition of human glioblastoma T98G cell proliferation in vitro. Peptides. 2010;31:1606–12.

    Article  CAS  PubMed  Google Scholar 

  5. Fujioka N, Nguyen J, Chen C, Li Y. Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer. Anesth Analg. 2011;113:1353–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Can Res. 2002;62:4491–8.

    CAS  Google Scholar 

  7. Leo S, Nuydens R, Meert TF. Opioid-induced proliferation of vascular endothelial cells. J Pain Res. 2009;2:59–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hatsukari I, Hitosugi N, Ohno R, Hashimoto K, Nakamura S, Satoh K, Nagasaka H, Matsumoto I, Sakagami H. Induction of apoptosis by morphine in human tumor cell lines in vitro. Anticancer Res. 2007;27:857–64.

    CAS  PubMed  Google Scholar 

  9. Koodie L, Ramakrishnan S, Roy S. Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway. AJP. 2010;177:984–97.

    CAS  PubMed  Google Scholar 

  10. Zagon IS, McLaughlin PJ. Opioids and the apoptotic pathway in human cancer cells. Neuropeptides. 2003;2:79–88.

    Article  CAS  Google Scholar 

  11. Qin Y, Chen J, Li L, Liao CJ, Liang YB, Guan EJ, Xie YB. Exogenous morphine inhibits human gastric cancer MGC- 803 cell growth by cell cycle arrest and apoptosis induction. Asian Pac J Cancer Prev. 2012;13:1377–82.

    Article  PubMed  Google Scholar 

  12. Yifeng X, Narayana Y, Mathias L, Eugene K, Yonghui Z, Eric O, Reuben JS, Inder MV. Reduced cell proliferation by IKK2 depletion in a mouse lung cancer model. Nat Cell Biol. 2012;14:257–65.

    Article  CAS  Google Scholar 

  13. Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF-kB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 2001; 20: 4188–97.

  14. Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res. 2008;14:6371–5.

    Article  CAS  PubMed  Google Scholar 

  15. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.

    Article  CAS  PubMed  Google Scholar 

  16. Sueoka E, Sueoka N, Kai Y, Okabe S, Suganuma M, Kanematsu K, Yamamoto T, Fujiki H. Anticancer activity of morphine and its synthetic derivative, KT-90, mediated through apoptosis and inhibition of NF-kappaB activation. Biochem Biophys Res Commun. 1998;252:566–70.

    Article  CAS  PubMed  Google Scholar 

  17. Wang K, Qu X, Wang Y, Shen H, Liu Q, Du J. Effect of mu agonists on long-term survival and recurrence in nonsmall cell lung cancer patients. Medicine. 2015;94:e1333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zylla D, Gourley BL, Vang D, Jackson S, Boatman S, Lindgren B, Kuskowski MA, Le C, Gupta K, Gupta P. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer. 2013;119:4103–10.

    Article  CAS  PubMed  Google Scholar 

  19. Lennon FE, Mirzapoiazova T, Mambetsariev B, Poroyko VA, Salgia R, Moss J, Singleton PA. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial mesenchymal transition (EMT) in human lung cancer. PLoS ONE. 2014;9:e91577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bimonte S, Barbieri A, Rea D, Palma G, Luciano A, Cuomo A, Arra C, Izzo F. Morphine promotes tumor angiogenesis and increases breast cancer progression. Biomed Res Int. 2015;2015:161508.

    PubMed  PubMed Central  Google Scholar 

  21. Roy S, Balasubramanian S, Wang J, Chandrashekhar Y, Charboneau R, Barke R. Morphine inhibits VEGF expression in myocardial ischemia. Surgery. 2003;134:336–44.

    Article  CAS  PubMed  Google Scholar 

  22. Balasubramanian S, Ramakrishnan S, Charboneau R, Wang J, Barke RA, Roy S. Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. J Mol Cell Cardiol. 2001;33:2179–87.

    Article  CAS  PubMed  Google Scholar 

  23. Borner C, Hollt V, Kraus J. Mechanisms of the Inhibition of nuclear factor- B by morphine in neuronal cells. Mol Pharmacol. 2012;81:587–97.

    Article  CAS  PubMed  Google Scholar 

  24. Popiolek-Barczyk K, Makuch W, Rojewska E, Pilat D, Mika J. Inhibition of intracellular signaling pathways NF-κB and MEK1/2 attenuates neuropathic pain development and enhances morphine analgesia. Pharmacol Rep. 2014;66:845–51.

    Article  CAS  PubMed  Google Scholar 

  25. Kraus J, Borner C, Giannini E, Hollt V. The role of nuclear factor b in tumor necrosis factor- regulated transcription of the human -opioid receptor gene. Mol Pharmacol. 2003;64:876–84.

    Article  CAS  PubMed  Google Scholar 

  26. Ye J, Yang Z, Li C, Cai M, Zhou D, Zhang Q, Wei Y, Wang T, Liu Y. NF-κB signaling and vesicle transport are correlated with the reactivation of the memory trace of morphine dependence. Diagn Pathol. 2014;9:142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Khan NI, Cisterne A, Baraz R, Bradstock KF, Bendall LJ. Para-NO-aspirin inhibits NF-κB and induces apoptosis in B-cell progenitor acute lymphoblastic leukemia. Exp Hematol. 2012;40:207–15.

    Article  CAS  PubMed  Google Scholar 

  28. Yin D, Woodruff M, Zhang Y, Whaley S, Miao J, Ferslew K, Zhao J, Stuart C. Morphine promotes Jurkat cell apoptosis through pro-apoptotic FADD/P53 and anti-apoptotic PI3K/Akt/NF-κB pathways. J Neuroimmunol. 2006;174:101–7.

    Article  CAS  PubMed  Google Scholar 

  29. Shibata A, Nagaya T, Imai T, Funahashi H, Nakao A, Seo H. Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells. Breast Cancer Res Treat. 2002;73:237–43.

    Article  CAS  PubMed  Google Scholar 

  30. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, Bessler H. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg. 1996;82(3):492–7.

    CAS  PubMed  Google Scholar 

  31. Forget P, Collet V, Lavand’homme P, DeKock M. Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages. Eur J Anaesthesiol 2010; 27(3): 233–40.

  32. Long X, Li Y, Qiu S, Liu J, He L, Peng Y. MiR-582-5p/miR-590-5p targeted CREB1/CREB5-NF-κB signaling and caused opioid-induced immunosuppression in human monocytes. Transl Psychiatry. 2016;6:e757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by a Grant-in-Aid for Young Scientists (B) (No. 17K16751) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, Japan

    Tadashi Nishiwada, Yoshitaka Kawaraguchi, Keiko Uemura & Masahiko Kawaguchi

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  1. Tadashi Nishiwada
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  2. Yoshitaka Kawaraguchi
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  3. Keiko Uemura
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  4. Masahiko Kawaguchi
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Correspondence to Tadashi Nishiwada.

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Nishiwada, T., Kawaraguchi, Y., Uemura, K. et al. Morphine inhibits cell viability and growth via suppression of vascular endothelial growth factor in human oral cancer HSC-3 cells. J Anesth 33, 408–415 (2019). https://doi.org/10.1007/s00540-019-02645-1

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  • DOI: https://doi.org/10.1007/s00540-019-02645-1

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