Tramadol suppresses growth of orthotopic liver tumors via promoting M1 macrophage polarization in the tumor microenvironment

Athavale D, Chouhan S, Pandey V, Mayengbam SS, Singh S, Bhat MK (2018) Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9). Cancer Metab 6:16. https://doi.org/10.1186/s40170-018-0187-2. (PubMed PMID: 30386595)

Article  PubMed  PubMed Central  Google Scholar 

Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U (2005) Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 30:245–252. https://doi.org/10.1007/BF02703705. (PubMed PMID: 15886461)

Article  PubMed  Google Scholar 

Bruix J, Reig M, Sherman M (2016) Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology 150:835–853. https://doi.org/10.1053/j.gastro.2015.12.041. (PubMed PMID: 26795574)

Article  PubMed  Google Scholar 

Bussiere JL, Adler MW, Rogers TJ, Eisenstein TK (1993) Cytokine reversal of morphine-induced suppression of the antibody response. J Pharmacol Exp Ther 264:591–597 (PubMed PMID: 8437110)

PubMed  Google Scholar 

Canton M, Sanchez-Rodriguez R, Spera I, Venegas FC, Favia M, Viola A, Castegna A (2021) Reactive Oxygen Species in Macrophages: Sources and Targets. Front Immunol 12:734229. https://doi.org/10.3389/fimmu.2021.734229. (PubMed PMID: 34659222)

Article  PubMed  PubMed Central  Google Scholar 

Chen Y, Huang Y, Reiberger T, Duyverman AM, Huang P, Samuel R, Hiddingh L, Roberge S, Koppel C, Lauwers GY, Zhu AX, Jain RK, Duda DG (2014) Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59:1435–1447. https://doi.org/10.1002/hep.26790. (PubMed PMID: 24242874)

Article  PubMed  Google Scholar 

Chen D, Xie J, Fiskesund R, Dong W, Liang X, Lv J, Jin X, Liu J, Mo S, Zhang T, Cheng F, Zhou Y, Zhang H, Tang K, Ma J, Liu Y, Huang B (2018) Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. Nat Commun 9:873. https://doi.org/10.1038/s41467-018-03225-9. (PubMed PMID: 29491374)

Article  PubMed  PubMed Central  Google Scholar 

Cheng K, Cai N, Zhu J, Yang X, Liang H, Zhang W (2022) Tumor-associated macrophages in liver cancer: From mechanisms to therapy. Cancer Commun (lond) 42:1112–1140. https://doi.org/10.1002/cac2.12345. (PubMed PMID: 36069342)

Article  PubMed  Google Scholar 

Chouhan S, Singh S, Athavale D, Ramteke P, Pandey V, Joseph J, Mohan R, Shetty PK, Bhat MK (2016) Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4. Sci Rep 6:27558. https://doi.org/10.1038/srep27558. (PubMed PMID: 27272409)

Article  PubMed  PubMed Central  Google Scholar 

Chouhan S, Sawant M, Weimholt C, Luo J, Sprung RW, Terrado M, Mueller DM, Earp HS, Mahajan NP (2023) TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability. Autophagy 19:1000–1025. https://doi.org/10.1080/15548627.2022.2103961. (PubMed PMID: 35895804)

Article  PubMed  Google Scholar 

Chouhan S, Singh S, Athavale D, Ramteke P, Vanuopadath M, Nair BG, Nair SS, Bhat MK (2020) Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucosedependent alterations in reactive oxygen species, P-glycoprotein and DKK4. J Biosci 45. https://doi.org/10.1007/s12038-020-00065-y

Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Primary antitumor immune response mediated by CD4+ T cells. Immunity 22:371–383. https://doi.org/10.1016/j.immuni.2005.02.003. (PubMed PMID: 15780993)

Article  PubMed  Google Scholar 

Elnagar GM, Elseweidy MM, Mahmoud YK, Elkomy N, Althafar ZM, Alnomasy SF, Al-Gabri NA, Shawky M (2022) 10-Dehydrogingerdione attenuates tramadol-induced nephrotoxicity by modulating renal oxidative stress, inflammation and apoptosis in experimental rats: role of HO-1 activation and TLR4/NF-kappaB/ERK inhibition. Int J Mol Sci 23. https://doi.org/10.3390/ijms23031384

Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P (2002) The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol 129:18–24. https://doi.org/10.1016/s0165-5728(02)00165-0. (PubMed PMID: 12161016)

Article  PubMed  Google Scholar 

Godai K, Hasegawa-Moriyama M, Kurimoto T, Saito T, Yamada T, Sato T, Kojima M, Kanmura Y (2014) Peripheral administration of morphine attenuates postincisional pain by regulating macrophage polarization through COX-2-dependent pathway. Mol Pain 10:36. https://doi.org/10.1186/1744-8069-10-36. (PubMed PMID: 24928142)

Article  PubMed  PubMed Central  Google Scholar 

Hao X, Sun G, Zhang Y, Kong X, Rong D, Song J, Tang W, Wang X (2021) Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front Cell Dev Biol 9:775462. https://doi.org/10.3389/fcell.2021.775462. (PubMed PMID: 34869376)

Article  PubMed  PubMed Central  Google Scholar 

Huang YH, Sue SH, Wu ZS, Huang SM, Lee SY, Wu ZF (2022) Antitumorigenic Effect of Tramadol and Synergistic Effect With Doxorubicin in Human Breast Cancer Cells. Front Oncol 12:811716. https://doi.org/10.3389/fonc.2022.811716. (PubMed PMID: 35155248)

Article  PubMed  PubMed Central  Google Scholar 

Inan S, Torres-Huerta A, Jensen LE, Dun NJ, Cowan A (2019) Nalbuphine, a kappa opioid receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis. Eur J Pharmacol 864:172702. https://doi.org/10.1016/j.ejphar.2019.172702. (PubMed PMID: 31568781)

Article  PubMed  PubMed Central  Google Scholar 

Juhas U, Ryba-Stanislawowska M, Szargiej P, Mysliwska J (2015) Different pathways of macrophage activation and polarization. Postepy Hig Med Dosw (online) 69:496–502. https://doi.org/10.5604/17322693.1150133. (PubMed PMID: 25983288)

Article  PubMed  Google Scholar 

Kim MH, Oh JE, Park S, Kim JH, Lee KY, Bai SJ, Song H, Hwang HJ, Kim DW, Yoo YC (2019) Tramadol use is associated with enhanced postoperative outcomes in breast cancer patients: a retrospective clinical study with in vitro confirmation. Br J Anaesth 123:865–876. https://doi.org/10.1016/j.bja.2019.09.004. (PubMed PMID: 31591020)

Article  PubMed  Google Scholar 

Kim MH, Lee JR, Kim KJ, Jun JH, Hwang HJ, Lee W, Nam SH, Oh JE, Yoo YC (2021) Identification for antitumor effects of tramadol in a xenograft mouse model using orthotopic breast cancer cells. Sci Rep 11:22113. https://doi.org/10.1038/s41598-021-01701-9. (PubMed PMID: 34764420)

Article  PubMed  PubMed Central  Google Scholar 

Kulik L, El-Serag HB (2019) Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology 156(477–491):e471. https://doi.org/10.1053/j.gastro.2018.08.065. (PubMed PMID: 30367835)

Article  Google Scholar 

Liu YM, Zhu SM, Wang KR, Feng ZY, Chen QL (2008) Effect of tramadol on immune responses and nociceptive thresholds in a rat model of incisional pain. J Zhejiang Univ Sci B 9:895–902. https://doi.org/10.1631/jzus.B0820039. (PubMed PMID: 18988309)

Article  PubMed  PubMed Central  Google Scholar 

Liu LC, Wu ZS, Chen JL, Wu ZF, Lai HC, Huang YH (2022) Mitochondrial dysfunction involved in the cytotoxicity of tramadol in human endometrial carcinoma cells. Int J Mol Sci 24. https://doi.org/10.3390/ijms24010099

Mohamed HM, Mahmoud AM (2019) Chronic exposure to the opioid tramadol induces oxidative damage, inflammation and apoptosis, and alters cerebral monoamine neurotransmitters in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 110:239–247. https://doi.org/10.1016/j.biopha.2018.11.141. (PubMed PMID: 30508735)

Article  Google Scholar 

Mohammadnejad L, Soltaninejad K, Seyedabadi M, Ghasem Pouri SK, Shokrzadeh M, Mohammadi H (2021) Evaluation of mitochondrial dysfunction due to oxidative stress in therapeutic, toxic and lethal concentrations of tramadol. Toxicol Res (camb) 10:1162–1170. https://doi.org/10.1093/toxres/tfab096. (PubMed PMID: 34956619)

Article  PubMed  Google Scholar 

Molitor TW, Morilla A, Risdahl JM, Murtaugh MP, Chao CC, Peterson PK (1992) Chronic morphine administration impairs cell-mediated immune responses in swine. J Pharmacol Exp Ther 260:581–586. https://doi.org/10.1016/0192-0561(91)90338-8

Mousavi K, Manthari RK, Najibi A, Jia Z, Ommati MM, Heidari R (2021) Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury. Curr Res Pharmacol Drug Discov 2:100049. https://doi.org/10.1016/j.crphar.2021.100049. (PubMed PMID: 34909675)

Article  PubMed  PubMed Central  Google Scholar 

Olmezturk Karakurt TC, Eren N, Subasi F, Kuyrukluyildiz U, Coban TA, Suleyman H, Mokhtare B (2023) Effects of taxifolin on tramadol-induced oxidative and inflammatory liver injury in rats: an experimental study. Drug Chem Toxicol 1–6. https://doi.org/10.1080/01480545.2023.2199175

Ou DL, Chen CW, Hsu CL, Chung CH, Feng ZR, Lee BS, Cheng AL, Yang MH, Hsu C (2021) Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages. J Immunother Cancer 9. https://doi.org/10.1136/jitc-2020-001657

Pathan H, Williams J (2012) Basic opioid pharmacology: an update. Br J Pain 6:11–16. https://doi.org/10.1177/2049463712438493. (PubMed PMID: 26516461)

Article  PubMed  PubMed Central  Google Scholar 

Perez S, Rius-Perez S (2022) Macrophage polarization and reprogramming in acute inflammation: a redox perspective. Antioxidants (Basel) 11. https://doi.org/10.3390/antiox11071394

Preston KL, Jasinski DR, Testa M (1991) Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend 27:7–17. https://doi.org/10.1016/0376-8716(91)90081-9. (PubMed PMID: 2029860)

Article  PubMed  Google Scholar 

Qin Z, Blankenstein T (2000) CD4+ T cell–mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 12:677–686. https://doi.org/10.1016/s1074-7613(00)80218-6. (PubMed PMID: 10894167)

Article  PubMed  Google Scholar 

Sacerdote P, Manfredi B, Mantegazza P, Panerai AE (1997) Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study. Br J Pharmacol 121:834–840. https://doi.org/10.1038/sj.bjp.0701138. (PubMed PMID: 9208156)

Article  PubMed  PubMed Central  Google Scholar 

Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE (2000) The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 90:1411–1414. https://doi.org/10.1097/00000539-200006000-00028. (PubMed PMID: 10825330)

Article  PubMed  Google Scholar 

Sheweita SA, Almasmari AA, El-Banna SG (2018) Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants. PLoS ONE 13:e0202110. https://doi.org/10.1371/journal.pone.0202110. (PubMed PMID: 30110401)

Article  PubMed  PubMed Central  Google Scholar 

Shirzad H, Shahrani M, Rafieian-Kopaei M (2009) Comparison of morphine and tramadol effects on phagocytic activity of mice peritoneal phagocytes in vivo. Int Immunopharmacol 9:968–970. https://doi.org/10.1016/j.intimp.2009.04.002. (PubMed PMID: 19361579)

Article  PubMed  Google Scholar 

Sia D, Villanueva A, Friedman SL, Llovet JM (2017) Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis. Gastroenterology 152:745–761. https://doi.org/10.1053/j.gastro.2016.11.048. (PubMed PMID: 28043904)

Article 

Comments (0)

No login
gif