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Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Maprotiline Prompts an Antitumour Effect by Inhibiting PD-L1 Expression in Mice with Melanoma

Author(s): Lirui Liang, Yang Li, Yang Jiao, Chunjing Zhang, Mingguang Shao, Hanyu Jiang, Zunge Wu, Haoqi Chen, Jiaming Guo, Huijie Jia* and Tiesuo Zhao*

Volume 17, 2024

Published on: 13 October, 2023

Article ID: e18761429259562 Pages: 12

DOI: 10.2174/0118761429259562230925055749

open_access

Abstract

Background: Research has revealed that the expression of PD-L1 is significantly upregulated in tumour cells and that the binding of programmed cell death protein 1 (PD-1) to programmed cell death 1 ligand 1 (PD-L1) inhibits the response of T cells, thereby suppressing tumour immunity. Therefore, blocking PD-L1/PD-1 signalling has become an important target in clinical immunotherapy. Some old drugs, namely, non-anticancer drugs, have also been found to have antitumour effects, and maprotiline is one of them. Maprotiline is a tetracyclic antidepressant that has been widely used to treat depression. However, it has not yet been reported whether maprotiline can exert an antitumour effect on melanoma.

Objective: This study aimed to investigate the antitumour efficacy of maprotiline in mice with melanoma.

Methods: In this study, female C57BL/6 mice were used to establish a tumour-bearing animal model. After treatment with maprotiline, the survival rate of mice was recorded daily. The expression of relevant proteins was detected by Western blotting, the proportion of immune cells was detected by flow cytometry, and the infiltration of immune cells in tumour tissue was detected by immunofluorescence staining.

Results: Maprotiline was found to inhibit the proliferation and migration of B16 cells while increasing cell apoptosis. Importantly, treatment with maprotiline decreased the expression of PD-L1 and increased the proportion of CD4+ T cells, CD8+ T cells, and NK cells in the spleen. It also increased the infiltration of CD4+ and CD8+ T cells in tumour tissue.

Conclusion: Our research findings suggest that maprotiline enhances the antitumour immune response in mouse melanoma by inhibiting PD-L1 expression. This study may discover a new PD-L1 inhibitor, providing a novel therapeutic option for the clinical treatment of tumours.

Keywords: Maprotiline, Melanoma, PD-L1, Antitumour immune response, Tumor immunity, Mouse melanoma.

[1]
Ambrosi, L.; Khan, S.; Carvajal, R.D.; Yang, J. Novel targets for the treatment of melanoma. Curr. Oncol. Rep., 2019, 21(11), 97.
[http://dx.doi.org/10.1007/s11912-019-0849-4] [PMID: 31696329]
[2]
Jan, C. R.; Su, J. A.; Teng, C. C.; Sheu, M. L.; Lin, P. Y.; Chi, M. C.; Chang, C. H.; Liao, W. C.; Kuo, C. C.; Chou, C. T. Mechanism of maprotiline-induced apoptosis: Role of [Ca2+](i), ERK, JNK and caspase-3 signaling pathways. Toxicology, 2013, 304, 1-12.
[3]
Brandes, L.J.; Arron, R.J.; Bogdanovic, R.P.; Tong, J.; Zaborniak, C.L.; Hogg, G.R.; Warrington, R.C.; Fang, W.; LaBella, F.S. Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses. Cancer Res., 1992, 52(13), 3796-3800.
[PMID: 1617649]
[4]
Shapovalov, Y.; Zettel, M.; Spielman, S. C.; Amico-Ruvio, S. A.; Kelly, E. A.; Sipe, G. O.; Dickerson, I. M.; Majewska, A. K.; Brown, E. B. Fluoxetine modulates breast cancer metastasis to the brain in a murine model. BMC Cancer, 2014, 14, 598.
[http://dx.doi.org/10.1186/1471-2407-14-598]
[5]
Hsu, L. C.; Tu, H. F.; Hsu, F. T.; Yueh, P. F.; Chiang, I. T. Beneficial effect of fluoxetine on anti-tumor progression on hepatocellular carcinoma and non-small cell lung cancer bearing animal model. Biomed. Pharmacother., 2020, 126, 110054.
[6]
Zhao, T.; Wei, T.; Guo, J.; Wang, Y.; Shi, X.; Guo, S.; Jia, X.; Jia, H.; Feng, Z. PD-1-siRNA delivered by attenuated Salmonella enhances the antimelanoma effect of pimozide. Cell Death Dis., 2019, 10(3), 164.
[http://dx.doi.org/10.1038/s41419-019-1418-3] [PMID: 30778049]
[7]
Wernli, K.J.; Hampton, J.M.; Trentham-Dietz, A.; Newcomb, P.A. Antidepressant medication use and breast cancer risk. Pharmacoepidemiol. Drug Saf., 2009, 18(4), 284-290.
[http://dx.doi.org/10.1002/pds.1719] [PMID: 19226540]
[8]
Jabbour, E.; Ravandi, F.; Kebriaei, P.; Huang, X.; Short, N.J.; Thomas, D.; Sasaki, K.; Rytting, M.; Jain, N.; Konopleva, M.; Garcia-Manero, G.; Champlin, R.; Marin, D.; Kadia, T.; Cortes, J.; Estrov, Z.; Takahashi, K.; Patel, Y.; Khouri, M.R.; Jacob, J.; Garris, R.; O’Brien, S.; Kantarjian, H. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini–hyper-CVD for patients with relapsed or refractory philadelphia chromosome–negative acute lymphoblastic leukemia. JAMA Oncol., 2018, 4(2), 230-234.
[http://dx.doi.org/10.1001/jamaoncol.2017.2380] [PMID: 28859185]
[9]
Gruter, W.; Poldinger, W. Maprotiline. Mod. Probl. Pharmacopsychiatry, 1982, 18, 17-48.
[10]
Rafiee, L.; Hajhashemi, V.; Javanmard, S.H. Maprotiline inhibits COX2 and iNOS gene expression in lipopolysaccharide-stimulated U937 macrophages and carrageenan-induced paw edema in rats. Cent. Eur. J. Immunol., 2019, 44(1), 15-22.
[http://dx.doi.org/10.5114/ceji.2019.84011] [PMID: 31114432]
[11]
Alburquerque-González, B.; Bernabé-García, M.; Montoro-García, S.; Bernabé-García, Á.; Rodrigues, P.C.; Ruiz Sanz, J.; López-Calderón, F.F.; Luque, I.; Nicolas, F.J.; Cayuela, M.L.; Salo, T.; Pérez-Sánchez, H.; Conesa-Zamora, P. New role of the antidepressant imipramine as a Fascin1 inhibitor in colorectal cancer cells. Exp. Mol. Med., 2020, 52(2), 281-292.
[http://dx.doi.org/10.1038/s12276-020-0389-x] [PMID: 32080340]
[12]
Shu, X.; Sun, Y.; Sun, X.; Zhou, Y.; Bian, Y.; Shu, Z.; Ding, J.; Lu, M.; Hu, G. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis., 2019, 10(8), 577.
[http://dx.doi.org/10.1038/s41419-019-1813-9] [PMID: 31371719]
[13]
Cloonan, S.M.; Drozgowska, A.; Fayne, D.; Williams, D.C. The antidepressants maprotiline and fluoxetine have potent selective antiproliferative effects against Burkitt lymphoma independently of the norepinephrine and serotonin transporters. Leuk. Lymphoma, 2010, 51(3), 523-539.
[http://dx.doi.org/10.3109/10428190903552112] [PMID: 20141432]
[14]
Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science, 2018, 359(6382), 1350-1355.
[http://dx.doi.org/10.1126/science.aar4060] [PMID: 29567705]
[15]
Sun, C.; Mezzadra, R.; Schumacher, T.N. Regulation and function of the PD-L1 checkpoint. Immunity, 2018, 48(3), 434-452.
[http://dx.doi.org/10.1016/j.immuni.2018.03.014] [PMID: 29562194]
[16]
Zaremba, A.; Zimmer, L.; Griewank, K.G.; Ugurel, S.; Roesch, A.; Schadendorf, D.; Livingstone, E. Immuntherapie beim malignen melanom. Internist, 2020, 61(7), 669-675.
[http://dx.doi.org/10.1007/s00108-020-00812-1] [PMID: 32462249]
[17]
Kwak, G.; Kim, D.; Nam, G.; Wang, S.Y.; Kim, I.S.; Kim, S.H.; Kwon, I.C.; Yeo, Y. Programmed cell death protein ligand-1 silencing with polyethylenimine–dermatan sulfate complex for dual inhibition of melanoma growth. ACS Nano, 2017, 11(10), 10135-10146.
[http://dx.doi.org/10.1021/acsnano.7b04717] [PMID: 28985469]
[18]
Kale, V.P.; Habib, H.; Chitren, R.; Patel, M.; Pramanik, K.C.; Jonnalagadda, S.C.; Challagundla, K.; Pandey, M.K. Old drugs, new uses: Drug repurposing in hematological malignancies. Semin. Cancer Biol., 2020, 68, 242-248.
[PMID: 32151704]
[19]
Mudduluru, G.; Walther, W.; Kobelt, D.; Dahlmann, M.; Treese, C.; Assaraf, Y. G.; Stein, U. Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets. Drug Resist. Updat., 2016, 26, 10-27.
[20]
Gerhards, N. M.; Rottenberg, S. New tools for old drugs: Functional genetic screens to optimize current chemotherapy. Drug Resist. Updat., 2018, 36, 30-46.
[21]
Martens, S.; Hofmans, S.; Declercq, W.; Augustyns, K.; Vandenabeele, P. Inhibitors targeting RIPK1/RIPK3: Old and new drugs. Trends Pharmacol. Sci., 2020, 41(3), 209-224.
[http://dx.doi.org/10.1016/j.tips.2020.01.002] [PMID: 32035657]
[22]
Wang, Y.; Liu, W.; Liu, M.; Wang, H.; Zhou, L.; Chen, J.; Sun, H.; Wei, X.; Fan, M.; Yang, M.; Liu, Z.; Yang, Z.; Zhong, J.; Lu, C.; Zhao, T.; Jia, H. Nifuroxazide in combination with CpG ODN exerts greater efficacy against hepatocellular carcinoma. Int. Immunopharmacol., 2022, 108, 108911.
[http://dx.doi.org/10.1016/j.intimp.2022.108911]
[23]
Hsu, S.S.; Chen, W.C.; Lo, Y.K.; Cheng, J.S.; Yeh, J.H.; Cheng, H.H.; Chen, J.S.; Chang, H.T.; Jiann, B.P.; Huang, J.K.; Jan, C.R. Effect of the antidepressant maprotiline on Ca2+ movement and proliferation in human prostate cancer cells. Clin. Exp. Pharmacol. Physiol., 2004, 31(7), 444-449.
[http://dx.doi.org/10.1111/j.1440-1681.2004.04024.x] [PMID: 15236632]
[24]
Fan, Y.; Bergmann, A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell! Trends Cell Biol., 2008, 18(10), 467-473.
[http://dx.doi.org/10.1016/j.tcb.2008.08.001] [PMID: 18774295]
[25]
Hays, E.; Bonavida, B. YY1 regulates cancer cell immune resistance by modulating PD-L1 expression. Drug Resist. Updat., 2019, 43, 10-28.
[26]
Constantinidou, A.; Alifieris, C.; Trafalis, D. T. Targeting programmed cell death -1 (PD-1) and ligand (PD-L1): A new era in cancer active immunotherapy. Pharmacol. Ther., 2019, 194, 84-106.
[27]
Hermanowicz, J.; Sieklucka, B.; Nosek, K.; Pawlak, D. Intracellular mechanisms of tumor cells’ immunoresistance. Acta Biochim. Pol., 2020, 67(2), 143-148.
[PMID: 32320192]
[28]
Hu, Z.; Ye, L.; Xing, Y.; Hu, J.; Xi, T. Combined SEP and anti-PD-L1 antibody produces a synergistic antitumor effect in B16-F10 melanoma-bearing mice. Sci. Rep., 2018, 8(1), 217.
[http://dx.doi.org/10.1038/s41598-017-18641-y] [PMID: 29317734]
[29]
Liu, B.; Arakawa, Y.; Yokogawa, R.; Tokunaga, S.; Terada, Y.; Murata, D.; Matsui, Y.; Fujimoto, K.; Fukui, N.; Tanji, M.; Mineharu, Y.; Minamiguchi, S.; Miyamoto, S. PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes. PLoS One, 2018, 13(4), e0194594.
[http://dx.doi.org/10.1371/journal.pone.0194594] [PMID: 29617441]
[30]
Chabaud, M.; Paillon, N.; Gaus, K.; Hivroz, C. Mechanobiology of antigen-induced T cell arrest. Biol. Cell, 2020, 112(7), 196-212.
[http://dx.doi.org/10.1111/boc.201900093] [PMID: 32275779]
[31]
Melero, I.; Rouzaut, A.; Motz, G.T.; Coukos, G. T-cell and NK-cell infiltration into solid tumors: A key limiting factor for efficacious cancer immunotherapy. Cancer Discov., 2014, 4(5), 522-526.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0985] [PMID: 24795012]
[32]
Hsu, J.; Hodgins, J.J.; Marathe, M.; Nicolai, C.J.; Bourgeois-Daigneault, M.C.; Trevino, T.N.; Azimi, C.S.; Scheer, A.K.; Randolph, H.E.; Thompson, T.W.; Zhang, L.; Iannello, A.; Mathur, N.; Jardine, K.E.; Kirn, G.A.; Bell, J.C.; McBurney, M.W.; Raulet, D.H.; Ardolino, M. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest., 2018, 128(10), 4654-4668.
[http://dx.doi.org/10.1172/JCI99317] [PMID: 30198904]
[33]
Du, S.S.; Chen, G.W.; Yang, P.; Chen, Y.X.; Hu, Y.; Zhao, Q.Q.; Zhang, Y.; Liu, R.; Zheng, D.X.; Zhou, J.; Fan, J.; Zeng, Z.C. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation. Int. J. Radiat. Oncol. Biol. Phys., 2022, 112(5), 1243-1255.
[http://dx.doi.org/10.1016/j.ijrobp.2021.12.162] [PMID: 34986380]

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