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Therapeutic strategies for colorectal cancer: antitumor efficacy of dopamine D2 receptor antagonists

  • Received : 2024.04.17
  • Accepted : 2024.07.26
  • Published : 2024.10.15

Abstract

Colorectal cancer (CRC) is one of the leading causes of death, accounting for more than half a million deaths annually. Even worse, an increasing number of cancer cases are diagnosed yearly, and two and a half million new cancer cases are estimated to be diagnosed in 2035. Some antipsychotic drugs, especially those targeting dopamine receptor (DR) D2, demonstrated anticancer activity. Studies have revealed the potential of DRD2 antagonists as anticancer therapeutics, whether alone or as an adjuvant, in treating breast cancer, lung cancer, and others. Emerging evidences indicate DRD2 is involved in the CRC biology, and the association between DRD2 and CRC could be utilized in treating CRC. This study selected DRD2 antagonists with anticancer activity to elucidate the possibility of DRD2 antagonists as new therapeutics for treating CRC.

Keywords

Acknowledgement

This study was funded by Daegu Catholic University research grants in the year 2024.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249. https://doi.org/10.3322/caac.21660
  2. Gustavsson B, Carlsson G, Machover D, Petrelli N, Roth A, Schmoll HJ, Tveit KM, Gibson F (2015) A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer 14:1-10. https://doi.org/10.1016/j.clcc.2014.11.002
  3. Tharin Z, Blanc J, Alaoui IC, Bertaut A, Ghiringhelli F (2021) Influence of frst line chemotherapy strategy depending on primary tumor location in metastatic colorectal cancer. J Gastrointest Oncol 12:1509-1517. https://doi.org/10.21037/jgo-20-593
  4. Wouters OJ, McKee M, Luyten J (2020) Estimated research and development investment needed to bring a new medicine to market, 2009-2018. JAMA 323:844-853. https://doi.org/10.1001/jama.2020.1166
  5. Austin BA, Gadhia AD (2017) New therapeutic uses for existing drugs. Adv Exp Med Biol 1031:233-247. https://doi.org/10.1007/978-3-319-67144-4_14
  6. Zhou S, Wang F, Hsieh TC, Wu JM, Wu E (2013) Thalidomide-a notorious sedative to a wonder anticancer drug. Curr Med Chem 20:4102-4108. https://doi.org/10.2174/09298673113209990198
  7. Hargrave-Thomas E, Yu B, Reynisson J (2012) Serendipity in anticancer drug discovery. World J Clin Oncol 3:1-6. https://doi.org/10.5306/wjco.v3.i1.1
  8. Yang Y, Mamouni K, Li X, Chen Y, Kavuri S, Du Y, Fu H, Kucuk O, Wu D (2018) Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer. Mol Cancer Ther 17:1859-1870. https://doi.org/10.1158/1535-7163.MCT-17-1176
  9. Matt SM, Gaskill PJ (2020) Where is dopamine and how do immune cells see it? Dopamine-mediated immune cell function in health and disease. J Neuroimmune Pharmacol 15:114-164. https://doi.org/10.1007/s11481-019-09851-4
  10. Scheibner J, Trendelenburg AU, Hein L, Starke K, Blandizzi C (2002) Alpha 2-adrenoceptors in the enteric nervous system: a study in alpha 2A-adrenoceptor-defcient mice. Br J Pharmacol 135:697-704. https://doi.org/10.1038/sj.bjp.0704512
  11. Li ZS, Schmauss C, Cuenca A, Ratclife E, Gershon MD (2006) Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wildtype and knock-out mice. J Neurosci 26:2798-2807. https://doi.org/10.1523/JNEUROSCI.4720-05.2006
  12. Herak-Perkovic V, Grabarevic Z, Banic M, Anic B, Novosel V, Pogacnik M (2001) Effects of dopaminergic drugs on inflammatory bowel disease induced with 2,4-dinitrofuorbenzene in BALB/c mice. J Vet Pharmacol Ther 24:267-273. https://doi.org/10.1046/j.1365-2885.2001.00343.x
  13. Magro F, Vieira-Coelho MA, Fraga S, Serrao MP, Veloso FT, Ribeiro T, Soares-da-Silva P (2002) Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci 47:216-224. https://doi.org/10.1023/a:1013256629600
  14. Tolstanova G, Deng X, Ahluwalia A, Paunovic B, Prysiazhniuk A, Ostapchenko L, Tarnawski A, Sandor Z, Szabo S (2015) Role of dopamine and D2 dopamine receptor in the pathogenesis of inflammatory bowel disease. Dig Dis Sci 60:2963-2975. https://doi.org/10.1007/s10620-015-3698-5
  15. Kim KM, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG (2001) Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J Biol Chem 276:37409-37414. https://doi.org/10.1074/jbc.M106728200
  16. Mangili F, Giardino E, Treppiedi D, Barbieri AM, Catalano R, Locatelli M, Lania AG, Spada A, Arosio M, Mantovani G, Peverelli E (2021) Beta-arrestin 2 Is required for dopamine receptor type 2 inhibitory effects on AKT phosphorylation and cell proliferation in pituitary tumors. Neuroendocrinology 111:568-579. https://doi.org/10.1159/000509219
  17. Li J, Zhu S, Kozono D, Ng K, Futalan D, Shen Y, Akers JC, Steed T, Kushwaha D, Schlabach M, Carter BS, Kwon CH, Furnari F, Cavenee W, Elledge S, Chen CC (2014) Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma. Oncotarget 5:882-893. https://doi.org/10.18632/oncotarget.1801
  18. Sotnikova TD, Beaulieu JM, Barak LS, Wetsel WC, Caron MG, Gainetdinov RR (2005) Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease. PLoS Biol 3:e271. https://doi.org/10.1371/journal.pbio.0030271
  19. Fregeau MO, Carrier M, Guillemette G (2013) Mechanism of dopamine D2 receptor-induced Ca(2+) release in PC-12 cells. Cell Signal 25:2871-2877. https://doi.org/10.1016/j.cellsig.2013.08.021
  20. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798-809. https://doi.org/10.1038/nrc2734
  21. Tegowski M, Fan C, Baldwin AS (2018) Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G(1) arrest independent of DRD2. J Biol Chem 293:15977-15990. https://doi.org/10.1074/jbc.RA118.003719
  22. Gkouveris I, Nikitakis N, Karanikou M, Rassidakis G, Sklavounou A (2014) Erk1/2 activation and modulation of STAT3 signaling in oral cancer. Oncol Rep 32:2175-2182. https://doi.org/10.3892/or.2014.3440
  23. Dalton SO, Mellemkjaer L, Thomassen L, Mortensen PB, Johansen C (2005) Risk for cancer in a cohort of patients hospitalized for schizophrenia in Denmark, 1969-1993. Schizophr Res 75:315-324. https://doi.org/10.1016/j.schres.2004.11.009
  24. Driver JA, Logroscino G, Buring JE, Gaziano JM, Kurth T (2007) A prospective cohort study of cancer incidence following the diagnosis of Parkinson's disease. Cancer Epidemiol Biomarkers Prev 16:1260-1265. https://doi.org/10.1158/1055-9965.EPI-07-0038
  25. Mu J, Huang W, Tan Z, Li M, Zhang L, Ding Q, Wu X, Lu J, Liu Y, Dong Q, Xu H (2017) Dopamine receptor D2 is correlated with gastric cancer prognosis. Oncol Lett 13:1223-1227. https://doi.org/10.3892/ol.2017.5573
  26. Pierce SR, Fang Z, Yin Y, West L, Asher M, Hao T, Zhang X, Tucker K, Staley A, Fan Y, Sun W, Moore DT, Xu C, Tsai YH, Parker J, Prabhu VV, Allen JE, Lee D, Zhou C, Bae-Jump V (2021) Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer. J Exp Clin Cancer Res 40:61. https://doi.org/10.1186/s13046-021-01842-9
  27. Gholipour N, Ohradanova-Repic A, Ahangari G (2018) A novel report of MiR-4301 induces cell apoptosis by negatively regulating DRD2 expression in human breast cancer cells. J Cell Biochem 119:6408-6417. https://doi.org/10.1002/jcb.26577
  28. Weissenrieder JS, Neighbors JD, Mailman RB, Hohl RJ (2019) Cancer and the dopamine D(2) receptor: a pharmacological perspective. J Pharmacol Exp Ther 370:111-126. https://doi.org/10.1124/jpet.119.256818
  29. Clevenger CV, Rui H (2022) Breast cancer and prolactin-new mechanisms and models. Endocrinology 163. https://doi.org/10.1210/endocr/bqac122
  30. Nadal R (2001) Pharmacology of the atypical antipsychotic remoxipride, a dopamine D2 receptor antagonist. CNS Drug Rev 7:265-282. https://doi.org/10.1111/j.1527-3458.2001.tb00199.x
  31. Pornour M, Ahangari G, Hejazi SH, Deezagi A (2015) New perspective therapy of breast cancer based on selective dopamine receptor D2 agonist and antagonist effects on MCF-7 cell line. Recent Pat Anticancer Drug Discov 10:214-223. https://doi.org/10.2174/1574892810666150416111831
  32. Li J, Yao QY, Xue JS, Wang LJ, Yuan Y, Tian XY, Su H, Wang SY, Chen WJ, Lu W, Zhou TY (2017) Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. Acta Pharmacol Sin 38:1282-1296. https://doi.org/10.1038/aps.2017.24
  33. Tan Y, Sun R, Liu L, Yang D, Xiang Q, Li L, Tang J, Qiu Z, Peng W, Wang Y, Ye L, Ren G, Xiang T (2021) Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-kappaB signaling to trigger pyroptosis in breast cancer. Theranostics 11:5214-5231. https://doi.org/10.7150/thno.58322
  34. Spitz MR, Shi H, Yang F, Hudmon KS, Jiang H, Chamberlain RM, Amos CI, Wan Y, Cinciripini P, Hong WK, Wu X (1998) Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J Natl Cancer Inst 90:358-363. https://doi.org/10.1093/jnci/90.5.358
  35. Ishibashi M, Fujisawa M, Furue H, Maeda Y, Fukayama M, Yamaji T (1994) Inhibition of growth of human small cell lung cancer by bromocriptine. Cancer Res 54:3442-3446
  36. Hoeppner LH, Wang Y, Sharma A, Javeed N, Van Keulen VP, Wang E, Yang P, Roden AC, Peikert T, Molina JR, Mukhopadhyay D (2015) Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells. Mol Oncol 9:270-281. https://doi.org/10.1016/j.molonc.2014.08.008
  37. Wu XY, Zhang CX, Deng LC, Xiao J, Yuan X, Zhang B, Hou ZB, Sheng ZH, Sun L, Jiang QC, Zhao W (2018) Overexpressed D2 dopamine receptor inhibits non-small cell lung cancer progression through inhibiting NF-kappaB signaling pathway. Cell Physiol Biochem 48:2258-2272. https://doi.org/10.1159/000492644
  38. Roy S, Lu K, Nayak MK, Bhuniya A, Ghosh T, Kundu S, Ghosh S, Baral R, Dasgupta PS, Basu S (2017) Activation of D2 dopamine receptors in CD133+ve cancer stem cells in non-small cell lung carcinoma inhibits proliferation, clonogenic ability, and invasiveness of these cells. J Biol Chem 292:435-445. https://doi.org/10.1074/jbc.M116.748970
  39. Tutton PJ, Barkla DH (1987) Amine dependence of proliferative activity in two transplantable lines of mouse colonic carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol 53:161-165. https://doi.org/10.1007/BF02890239
  40. Iishi H, Baba M, Tatsuta M, Okuda S, Taniguchi H (1991) Inhibition by the dopamine antagonist haloperidol of experimental carcinogenesis induced by azoxymethane in rat colon. Cancer Res 51:6150-6152
  41. Basu S, Dasgupta PS (1999) Decreased dopamine receptor expression and its second-messenger cAMP in malignant human colon tissue. Dig Dis Sci 44:916-921. https://doi.org/10.1023/a:1026644110737
  42. Gemignani F, Landi S, Moreno V, Gioia-Patricola L, Chabrier A, Guino E, Navarro M, Cambray M, Capella G, Canzian F (2005) Polymorphisms of the dopamine receptor gene DRD2 and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 14:1633-1638. https://doi.org/10.1158/1055-9965.EPI-05-0057
  43. Kontos CK, Papadopoulos IN, Fragoulis EG, Scorilas A (2010) Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma. Br J Cancer 102:1384-1390. https://doi.org/10.1038/sj.bjc.6605654
  44. Kopljar M, Patrlj L, Korolija-Marinic D, Horzic M, Cupurdija K, Bakota B (2015) High expression of DARPP-32 in colorectal cancer is associated with liver metastases and predicts survival for Dukes A and B patients: results of a pilot study. Int Surg 100:213-220. https://doi.org/10.9738/INTSURG-D-14-00022.1
  45. He K, Xie CZ, Li Y, Chen ZZ, Xu SH, Huang SQ, Yang JG, Wei ZQ, Peng XD (2023) Dopamine and cyclic adenosine monophosphate-regulated phosphoprotein with an apparent Mr of 32000 promotes colorectal cancer growth. World J Gastrointest Oncol 15:1936-1950. https://doi.org/10.4251/wjgo.v15.i11.1936
  46. Lee WY, Lee WT, Cheng CH, Chen KC, Chou CM, Chung CH, Sun MS, Cheng HW, Ho MN, Lin CW (2015) Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1. Oncotarget 6:27580-27595. https://doi.org/10.18632/oncotarget.4768
  47. Zhang C, Gong P, Liu P, Zhou N, Zhou Y, Wang Y (2017) Thioridazine elicits potent antitumor effects in colorectal cancer stem cells. Oncol Rep 37:1168-1174. https://doi.org/10.3892/or.2016.5313
  48. Tran TH, Kao M, Liu HS, Hong YR, Su Y, Huang CF (2023) Repurposing thioridazine for inducing immunogenic cell death in colorectal cancer via eIF2alpha/ATF4/CHOP and secretory autophagy pathways. Cell Commun Signal 21:184. https://doi.org/10.1186/s12964-023-01190-5
  49. Sim SJ, Jang JH, Choi JS, Chun KS (2024) Domperidone, a dopamine receptor D2 antagonist, induces apoptosis by inhibiting the ERK/STAT3-mediated pathway in human colon cancer HCT116 cells. Biomol Ther. https://doi.org/10.4062/biomolther.2024.048 [Online ahead of print]
  50. Bergin CJ, Zouggar A, Mendes da Silva A, Fenouil T, Haebe JR, Masibag AN, Agrawal G, Shah MS, Sandouka T, Tiberi M, Auer RC, Ardolino M, Benoit YD (2024) The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors. Nat Cancer 5:463-480. https://doi.org/10.1038/s43018-024-00727-y
  51. Thanacoody RH (2011) Thioridazine: the good and the bad. Recent Pat Antiinfect Drug Discov 6:92-98. https://doi.org/10.2174/157489111796064588
  52. Chu CW, Ko HJ, Chou CH, Cheng TS, Cheng HW, Liang YH, Lai YL, Lin CY, Wang C, Loh JK, Cheng JT, Chiou SJ, Su CL, Huang CF, Hong YR (2019) Thioridazine enhances P62-mediated autophagy and apoptosis through WNT/beta-catenin signaling pathway in glioma cells. Int J Mol Sci 20:473. https://doi.org/10.3390/ijms20030473
  53. Mao M, Yu T, Hu J, Hu L (2015) Dopamine D2 receptor blocker thioridazine induces cell death in human uterine cervical carcinoma cell line SiHa. J Obstet Gynaecol Res 41:1240-1245. https://doi.org/10.1111/jog.12691
  54. Kang S, Dong SM, Kim BR, Park MS, Trink B, Byun HJ, Rho SB (2012) Thioridazine induces apoptosis by targeting the PI3K/Akt/mTOR pathway in cervical and endometrial cancer cells. Apoptosis 17:989-997. https://doi.org/10.1007/s10495-012-0717-2
  55. Moraes VWR, Santos VM, Suarez ER, Ferraz LS, Lopes RM, Mognol GP, Campeiro JD, Machado-Neto JA, Nascimento FD, Hayashi MAF, Tersariol ILS, Newmeyer DD, Rodrigues T (2022) Targeting Ca(2+) and mitochondrial homeostasis by antipsychotic thioridazine in leukemia cells. Life 12:1477. https://doi.org/10.3390/life12101477
  56. Lopez-Munoz F, Alamo C (2009) The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice. Brain Res Bull 79:130-141. https://doi.org/10.1016/j.brainresbull.2009.01.005
  57. Vlachos N, Lampros M, Voulgaris S, Alexiou GA (2021) Repurposing antipsychotics for cancer treatment. Biomedicines 9:1785. https://doi.org/10.3390/biomedicines9121785
  58. Shi L, Chen H, Chen K, Zhong C, Song C, Huang Y, Wang T, Chen L, Li C, Huang A, Qi S, Li H, Lu Y (2023) The DRD2 antagonist haloperidol mediates autophagy-induced ferroptosis to increase temozolomide sensitivity by promoting endoplasmic reticulum stress in glioblastoma. Clin Cancer Res 29:3172-3188. https://doi.org/10.1158/1078-0432.CCR-22-3971
  59. Barone JA (1999) Domperidone: a peripherally acting dopamine2-receptor antagonist. Ann Pharmacother 33:429-440. https://doi.org/10.1345/aph.18003
  60. Shakya R, Byun MR, Joo SH, Chun KS, Choi JS (2023) Domperidone exerts antitumor activity in triple-negative breast cancer cells by modulating reactive oxygen species and JAK/STAT3 signaling. Biomol Ther 31:692-699. https://doi.org/10.4062/biomolther.2023.173
  61. Laskowska AK, Kleczkowska P (2022) Anticancer efficacy of endo- and exogenous potent ligands acting at dopaminergic receptor-expressing cancer cells. Eur J Pharmacol 932:175230. https://doi.org/10.1016/j.ejphar.2022.175230
  62. Kline CLB, Ralf MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, Allen JE, El-Deiry WS (2018) Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia 20:80-91. https://doi.org/10.1016/j.neo.2017.10.002