Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression
,
Abstract
Background: We aimed to explore the mechanism of the effect of remimazolam (Rem) on the proliferation of colorectal cancer (CRC) cells with CRC as a disease context.
Methods: Translocation protein (TSPO) expression in CRC was determined by Western blotting and qRT-PCR in the Second Affiliated Hospital of Qiqihar Medical University from March 2019 to February 2022. TSPO-interacting proteins were predicted through string database. The proliferation was measured by CCK-8 and 5-ethynyl-2-deoxyuridine (EDU). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) and clonal colony on cells were formed to screen for the optimal concentration of Rem and to detect the viability. The expression of apoptosis-related proteins, Bcl-2 and P53, was determined by qRT-PCR and Western blotting. The effect of Rem on the expression of tumor markers, CEA and CA19-9, in CRC was examined through ELISA.
Results: TSPO expression in CRC tissues and cells was higher than that in ANT samples and normal intestinal epithelial cells. Over-expression of TSPO promoted the proliferation of HCT116 and the expression of tumor markers CEA and CA19-9 and inhibited the apoptosis of HCT116. Interference with TSPO inhibited the proliferation of HCT116 and the expression of CEA and CA19-9 and promoted the apoptosis of HCT116. 1 μg/mL Rem could inhibit the viability of HCT116, the proliferation of HCT116 and the expression of CEA and CA19-9, and improve the apoptosis of HCT116. TSPO could interact with VDAC and affect its protein expression, and Rem could inhibit the proliferation and the expression of CEA and CA19-9 through the TSPO/VDAC pathway, to promote its apoptosis.
Conclusion: Rem affects the proliferation of CRC cells by inhibiting the TSPO/VDAC pathway.
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16. Zhou XW, Ma Z, Geng T, Wang ZZ, Ding G, Yu-an B, Xiao W (2014). Evaluation of in vitro inhibition and induction of cytochrome P450 activities by hydro-lyzed ginkgolides. J Ethnopharmacol, 158 Pt A:132-9.
17. Kimani MM, Lanzarotta A, Batson JS (2021). Rapid determination of eight benzodiazepines in suspected counter-feit pharmaceuticals using surface-enhanced Raman scattering with handheld Raman spectrometers. J Foren-sic Sci, 66(6):2167-2179.
18. Chen X, Sang N, Song K, et al (2020). Psy-chomotor Recovery Following Remi-mazolam-induced Sedation and the Ef-fectiveness of Flumazenil as an Anti-dote. Clin Ther, 42(4):614-624.
19. Zhou J, Leonowens C, Ivaturi VD, et al (2020). Population pharmacokinet-ic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects. J Clin Anesth, 66:109899.
20. Rawla P, Sunkara T, Barsouk A (2019). Epi-demiology of colorectal cancer: inci-dence, mortality, survival, and risk fac-tors. Prz Gastroenterol, 14(2):89-103.
21. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019). Colorectal cancer. Lancet, 394(10207):1467-1480.
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23. Taieb J, Balogoun R, Le Malicot K, (2017). Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients. Ann Oncol, 28(4):824-830.
24. Siegel RL, Miller KD, Jemal A (2019). Can-cer statistics, 2019. CA Cancer J Clin, 69(1):7-34.
25. Wolf AMD, Fontham ETH, Church TR, et al (2018). Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Soci-ety. CA Cancer J Clin, 68(4):250-281.
26. Xie YH, Chen YX, Fang JY (2020). Com-prehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther, 5(1):22.
27. Sneyd JR, Rigby-Jones AE (2020). Remima-zolam for anaesthesia or sedation. Curr Opin Anaesthesiol, 33(4):506-511.
28. Bonsack F, Sukumari-Ramesh S (2018). TSPO: An Evolutionarily Conserved Protein with Elusive Functions. Int J Mol Sci, 19(6):1694.
29. Gatliff J, Campanella M (2015). TSPO is a REDOX regulator of cell mitophagy. Biochem Soc Trans, 43(4):543-52.
30. Fiorenza D, Nicolai E, Cavaliere C, Fiori-no F, Esposito G, Salvatore M (2021). Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam. Molecules, 26(8):2372.
31. Fernández Hurst N, Zanetti SR, Báez NS, Bibolini MJ, Bouzat C, Roth GA (2017). Diazepam treatment reduces inflamma-tory cells and mediators in the central nervous system of rats with experi-mental autoimmune encephalomyelitis. J Neuroimmunol, 313:145-151.
32. Rupprecht R, Rammes G, Eser D, et al (2009). Translocator protein (18 kD) as target for anxiolytics without benzodi-azepine-like side effects. Science, 325(5939):490-3.
33. Reinsalu L, Puurand M, Chekulayev V, et al (2021). Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determi-nant of Tumor Growth and Metastasis. Front Oncol, 11:698951.
34. Ounpuu L, Truu L, Shevchuk I, et al (2018). Comparative analysis of the bioenerget-ics of human adenocarcinoma Caco-2 cell line and postoperative tissue sam-ples from colorectal cancer patients. Bi-ochem Cell Biol, 30:1-10.
35. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V (2014). Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo. Mol Ther Nucleic Acids, 3(4):e159.
36. Gupta R, Ghosh S (2017). Putative roles of mitochondrial Voltage-Dependent Ani-on Channel, Bcl-2 family proteins and c-Jun N-terminal Kinases in ischemic stroke associated apoptosis. Biochim Open, 4:47-55.
2. Johdi NA, Sukor NF (2020). Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol, 11:1624.
3. Lech G, Słotwiński R, Słodkowski M, Kras-nodębski IW (2016). Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances. World J Gastroenter-ol, 22(5):1745-55.
4. Maaser K, Grabowski P, Sutter AP, et al (2002). Overexpression of the peripheral benzodiazepine receptor is a relevant prognostic factor in stage III colorectal cancer. Clin Cancer Res, 8(10):3205-9.
5. Zhang L, Hu K, Shao T, et al (2021). Recent developments on PET radiotracers for TSPO and their applications in neu-roimaging. Acta Pharm Sin B, 11(2):373-393.
6. Jia JB, Ling X, Xing M, Ludwig JM, Bai M, Kim HS (2020). Novel TSPO-targeted Doxorubicin Prodrug for Colorectal Carcinoma Cells. Anticancer Res, 40(10):5371-5378.
7. Shoukrun R, Veenman L, Shandalov Y, et al (2008). The 18-kDa translocator protein, formerly known as the peripheral-type benzodiazepine receptor, confers proapoptotic and antineoplastic effects in a human colorectal cancer cell line. Pharmacogenet Genomics, 18(11):977-88.
8. Garnier M, Dimchev AB, Boujrad N, Price JM, Musto NA, Papadopoulos V (1994). In vitro reconstitution of a functional peripheral-type benzodiazepine recep-tor from mouse Leydig tumor cells. Mol Pharmacol, 45(2):201-11.
9. Halestrap AP, McStay GP, Clarke SJ (2002). The permeability transition pore com-plex: another view. Biochimie, 84(2-3):153-66.
10. Barresi E, Robello M, Costa B, et al (2021). An update into the medicinal chemistry of translocator protein (TSPO) ligands. Eur J Med Chem, 209:112924.
11. Kilpatrick GJ (2021). Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent. Front Pharma-col, 12:690875..
12. Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM (2012). A pla-cebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and phar-macodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg, 115(2):274-83.
13. Yang M, Liu X, Yang D, Bai Y, Qin B, Tian S, Dong R, Song X (2021). Effect of rem-imazolam besylate compared with propofol on the incidence of delirium after cardiac surgery: study protocol for a randomized trial. Trials, 22(1):717.
14. Zhang X, Li S, Liu J (2021). Efficacy and safety of remimazolam besylate versus propofol during hysteroscopy: single-centre randomized controlled trial. BMC Anesthesiol, 21(1):156.
15. Sheng XY, Liang Y, Yang XY, Li LE, Ye X, Zhao X, Cui YM (2020). Safety, pharma-cokinetic and pharmacodynamic prop-erties of single ascending dose and con-tinuous infusion of remimazolam besyl-ate in healthy Chinese volunteers. Eur J Clin Pharmacol, 76(3):383-391.
16. Zhou XW, Ma Z, Geng T, Wang ZZ, Ding G, Yu-an B, Xiao W (2014). Evaluation of in vitro inhibition and induction of cytochrome P450 activities by hydro-lyzed ginkgolides. J Ethnopharmacol, 158 Pt A:132-9.
17. Kimani MM, Lanzarotta A, Batson JS (2021). Rapid determination of eight benzodiazepines in suspected counter-feit pharmaceuticals using surface-enhanced Raman scattering with handheld Raman spectrometers. J Foren-sic Sci, 66(6):2167-2179.
18. Chen X, Sang N, Song K, et al (2020). Psy-chomotor Recovery Following Remi-mazolam-induced Sedation and the Ef-fectiveness of Flumazenil as an Anti-dote. Clin Ther, 42(4):614-624.
19. Zhou J, Leonowens C, Ivaturi VD, et al (2020). Population pharmacokinet-ic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects. J Clin Anesth, 66:109899.
20. Rawla P, Sunkara T, Barsouk A (2019). Epi-demiology of colorectal cancer: inci-dence, mortality, survival, and risk fac-tors. Prz Gastroenterol, 14(2):89-103.
21. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019). Colorectal cancer. Lancet, 394(10207):1467-1480.
22. Wang H (2020). MicroRNAs and Apoptosis in Colorectal Cancer. Int J Mol Sci, 21(15):5353.
23. Taieb J, Balogoun R, Le Malicot K, (2017). Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients. Ann Oncol, 28(4):824-830.
24. Siegel RL, Miller KD, Jemal A (2019). Can-cer statistics, 2019. CA Cancer J Clin, 69(1):7-34.
25. Wolf AMD, Fontham ETH, Church TR, et al (2018). Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Soci-ety. CA Cancer J Clin, 68(4):250-281.
26. Xie YH, Chen YX, Fang JY (2020). Com-prehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther, 5(1):22.
27. Sneyd JR, Rigby-Jones AE (2020). Remima-zolam for anaesthesia or sedation. Curr Opin Anaesthesiol, 33(4):506-511.
28. Bonsack F, Sukumari-Ramesh S (2018). TSPO: An Evolutionarily Conserved Protein with Elusive Functions. Int J Mol Sci, 19(6):1694.
29. Gatliff J, Campanella M (2015). TSPO is a REDOX regulator of cell mitophagy. Biochem Soc Trans, 43(4):543-52.
30. Fiorenza D, Nicolai E, Cavaliere C, Fiori-no F, Esposito G, Salvatore M (2021). Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam. Molecules, 26(8):2372.
31. Fernández Hurst N, Zanetti SR, Báez NS, Bibolini MJ, Bouzat C, Roth GA (2017). Diazepam treatment reduces inflamma-tory cells and mediators in the central nervous system of rats with experi-mental autoimmune encephalomyelitis. J Neuroimmunol, 313:145-151.
32. Rupprecht R, Rammes G, Eser D, et al (2009). Translocator protein (18 kD) as target for anxiolytics without benzodi-azepine-like side effects. Science, 325(5939):490-3.
33. Reinsalu L, Puurand M, Chekulayev V, et al (2021). Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determi-nant of Tumor Growth and Metastasis. Front Oncol, 11:698951.
34. Ounpuu L, Truu L, Shevchuk I, et al (2018). Comparative analysis of the bioenerget-ics of human adenocarcinoma Caco-2 cell line and postoperative tissue sam-ples from colorectal cancer patients. Bi-ochem Cell Biol, 30:1-10.
35. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V (2014). Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo. Mol Ther Nucleic Acids, 3(4):e159.
36. Gupta R, Ghosh S (2017). Putative roles of mitochondrial Voltage-Dependent Ani-on Channel, Bcl-2 family proteins and c-Jun N-terminal Kinases in ischemic stroke associated apoptosis. Biochim Open, 4:47-55.
| Files | ||
| Issue | Vol 52 No 7 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i7.13239 | |
| Keywords | ||
| Colorectal cancer Remimazolam Translocation protein | ||
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How to Cite
1.
Liu Y, Wang S, Yang W. Inhibiting the Proliferation of Colorectal Cancer Cells by Reducing TSPO/VDAC Expression. Iran J Public Health. 2023;52(7):1378-1389.
