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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

An Antidepressant Drug Increased TRAIL Receptor-2 Expression and Sensitized Lung Cancer Cells to TRAIL-induced Apoptosis

Author(s): Kazi Mohammad Ali Zinnah, Ali Newaz Munna, Jae-Won Seol, Byung-Yong Park and Sang-Youel Park*

Volume 23, Issue 20, 2023

Published on: 06 October, 2023

Page: [2225 - 2236] Pages: 12

DOI: 10.2174/0118715206262252231004110310

open access plus


Background: TRAIL has emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells while sparing normal cells. Autophagy, a highly regulated cellular recycling mechanism, is known to play a cell survival role by providing a required environment for the cell. Recent studies suggest that autophagy plays a significant role in increasing TRAIL resistance in certain cancer cells. Thus, regulating autophagy in TRAIL-mediated cancer therapy is crucial for its role in cancer treatment.

Objective: Our study explored whether the antidepressant drug desipramine could enhance the ability of TRAIL to kill cancer cells by inhibiting autophagy.

Methods: The effect of desipramine on TRAIL sensitivity was examined in various lung cancer cell lines. Cell viability was measured by morphological analysis, trypan blue exclusion, and crystal violet staining. Flow cytometry analysis was carried out to measure apoptosis with annexin V-PI stained cells. Western blotting, rtPCR, and immunocytochemistry were carried out to measure autophagy and death receptor expression. TEM was carried out to detect autophagy inhibition.

Results: Desipramine treatment increased the TRAIL sensitivity in all lung cancer cell lines. Mechanistically, desipramine treatment induced death receptor expression to increase TRAIL sensitivity. This effect was confirmed when the genetic blockade of DR5 reduced the effect of desipramine in enhanced TRAIL-mediated cell death. Further investigation revealed that desipramine treatment increased the LC3 and p62 levels, indicating the inhibition of lysosomal degradation of autophagy. Notably, TRAIL, in combination with either desipramine or the autophagy inhibitor chloroquine, exhibited enhanced cytotoxicity compared to TRAIL treatment alone.

Conclusion: Our findings revealed the potential of desipramine to induce TRAIL-mediated cell death by autophagy impairment. This discovery suggests its therapeutic potential for inducing TRAIL-mediated cell death by increasing the expression of death receptors, which is caused by impairing autophagy.

Keywords: Desipramine, autophagy, apoptosis, death receptor-5, TRAIL, antidepressant drug.

Graphical Abstract
Dela Cruz, C.S.; Tanoue, L.T.; Matthay, R.A. Lung cancer: Epidemiology, etiology, and prevention. Clin. Chest Med., 2011, 32(4), 605-644.
[] [PMID: 22054876]
Chaitanya, T.K.; Barsouk, A.; Saginala, K.; Sukumar, A.J.; Barsouk, A. Epidemiology of lung cancer. Contemp. Oncol., 2021, 25(1), 45-52.
[] [PMID: 33911981]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[] [PMID: 30620402]
Lin, C.; Lin, X.; Lin, K.; Tan, J.; Wei, C.; Liu, T. LKB1 expression and the prognosis of lung cancer. Medicine , 2021, 100(46), e27841.
[] [PMID: 34797317]
Hirsch, F.R.; Scagliotti, G.V.; Mulshine, J.L.; Kwon, R.; Curran, W.J., Jr; Wu, Y.L.; Paz-Ares, L. Lung cancer: Current therapies and new targeted treatments. Lancet, 2017, 389(10066), 299-311.
[] [PMID: 27574741]
Huang, C.Y.; Ju, D.T.; Chang, C.F.; Muralidhar Reddy, P.; Velmurugan, B.K. A review on the effects of current chemotherapy drugs and natural agents in treating non–small cell lung cancer. Biomedicine, 2017, 7(4), 23-23.
[] [PMID: 29130448]
Silva, A.P.S.; Coelho, P.V.; Anazetti, M.; Simioni, P.U. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors. Hum. Vaccin. Immunother., 2017, 13(4), 843-853.
[] [PMID: 27831000]
Mokhtari, R.B.; Homayouni, T.S.; Baluch, N.; Morgatskaya, E.; Kumar, S.; Das, B.; Yeger, H. Combination therapy in combating cancer. Oncotarget, 2017, 8(23), 38022-38043.
[] [PMID: 28410237]
Debela, D.T.; Muzazu, S.G.Y.; Heraro, K.D.; Ndalama, M.T.; Mesele, B.W.; Haile, D.C.; Kitui, S.K.; Manyazewal, T. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med., 2021, 9, 20503121211034366.
[] [PMID: 34408877]
Valley, C.C.; Lewis, A.K.; Mudaliar, D.J.; Perlmutter, J.D.; Braun, A.R.; Karim, C.B.; Thomas, D.D.; Brody, J.R.; Sachs, J.N. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor 5 networks that are highly organized. J. Biol. Chem., 2012, 287(25), 21265-21278.
[] [PMID: 22496450]
Griffith, T.; Stokes, B.; Kucaba, T.; Earel, J., Jr; VanOosten, R.; Brincks, E.; Norian, L. TRAIL gene therapy: From preclinical development to clinical application. Curr. Gene Ther., 2009, 9(1), 9-19.
[] [PMID: 19275567]
Kadowaki, Y.; Chari, N.S.; Teo, A.E.K.; Hashi, A.; Spurgers, K.B.; McDonnell, T.J. PI3 Kinase inhibition on TRAIL-induced apoptosis correlates with androgen-sensitivity and p21 expression in prostate cancer cells. Apoptosis, 2011, 16(6), 627-635.
[] [PMID: 21437722]
Fossati, S.; Ghiso, J.; Rostagno, A. TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer’s Aβ. Cell Death Dis., 2012, 3(6), e321-e321.
[] [PMID: 22695614]
Reis, C.R.; Chen, P.H.; Bendris, N.; Schmid, S.L. TRAIL-death receptor endocytosis and apoptosis are selectively regulated by dynamin-1 activation. Proc. Natl. Acad. Sci. , 2017, 114(3), 504-509.
[] [PMID: 28049841]
Wang, S.; El-Deiry, W.S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene, 2003, 22(53), 8628-8633.
[] [PMID: 14634624]
Dai, X.; Zhang, J.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Kumar, A.P.; Ahn, K.S.; Sethi, G. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp. Biol. Med. , 2015, 240(6), 760-773.
[] [PMID: 25854879]
Zhang, L.; Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther., 2005, 12(3), 228-237.
[] [PMID: 15550937]
Huang, Y.; Yang, X.; Xu, T.; Kong, Q.; Zhang, Y.; Shen, Y.; Wei, Y.; Wang, G.; Chang, K.J. Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. Int. J. Oncol., 2016, 49(1), 153-163.
[] [PMID: 27210546]
Guo, Z.L.; Li, J.Z.; Ma, Y.Y.; Qian, D.; Zhong, J.Y.; Jin, M.M.; Huang, P.; Che, L.Y.; Pan, B.; Wang, Y.; Sun, Z.X.; Liu, C.Z. Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways. BMC Cell Biol., 2018, 19(1), 29-29.
[] [PMID: 30594131]
Li, X.; You, M.; Liu, Y.; Ma, L.; Jin, P.; Zhou, R.; Zhang, Z.X.; Hua, B.; Ji, X.; Cheng, X.; Yin, F.; Chen, Y.; Yin, W. Reversal of the apoptotic resistance of non-small-cell lung carcinoma towards TRAIL by natural product toosendanin. Sci. Rep., 2017, 7(1), 42748-42748.
[] [PMID: 28209994]
Trivedi, R.; Mishra, D.P. Trailing TRAIL resistance: Novel targets for TRAIL sensitization in cancer cells. Front. Oncol., 2015, 5, 69-69.
[] [PMID: 25883904]
Yonekawa, T.; Thorburn, A. Autophagy and cell death. Essays Biochem., 2013, 55, 105-117.
[] [PMID: 24070475]
Han, H.; Zhou, H.; Li, J.; Feng, X.; Zou, D.; Zhou, W. TRAIL DR5-CTSB crosstalk participates in breast cancer autophagy initiated by SAHA. Cell Death Discov., 2017, 3(1), 17052.
[] [PMID: 29018571]
Kroemer, G.; Mariño, G.; Levine, B. Autophagy and the integrated stress response. Mol. Cell, 2010, 40(2), 280-293.
[] [PMID: 20965422]
Russell, R.C.; Guan, K.L. The multifaceted role of autophagy in cancer. EMBO J., 2022, 41(13), e110031.
[] [PMID: 35535466]
Zhao, Y.G.; Zhang, H. Autophagosome maturation: An epic journey from the ER to lysosomes. J. Cell Biol., 2019, 218(3), 757-770.
[] [PMID: 30578282]
Yu, L.; Chen, Y.; Tooze, S.A. Autophagy pathway: Cellular and molecular mechanisms. Autophagy, 2018, 14(2), 207-215.
[] [PMID: 28933638]
Giménez-Xavier, P.; Francisco, R.; Platini, F.; Pérez, R.; Ambrosio, S. LC3-I conversion to LC3-II does not necessarily result in complete autophagy. Int. J. Mol. Med., 2008, 22(6), 781-785.
[PMID: 19020776]
Tanida, I.; Ueno, T.; Kominami, E. LC3 and autophagy. Methods Mol. Biol., 2008, 445, 77-88.
[] [PMID: 18425443]
Huang, Z.; Gan, S.; Zhuang, X.; Chen, Y.; Lu, L.; Wang, Y.; Qi, X.; Feng, Q.; Huang, Q.; Du, B.; Zhang, R.; Liu, Z. Artesunate inhibits the cell growth in colorectal cancer by promoting ROS-dependent cell senescence and autophagy. Cells, 2022, 11(16), 2472.
[] [PMID: 36010550]
Ma, S.; Attarwala, I.Y.; Xie, X.Q. SQSTM1/p62: A potential target for neurodegenerative disease. ACS Chem. Neurosci., 2019, 10(5), 2094-2114.
[] [PMID: 30657305]
Zhang, Z.; Singh, R.; Aschner, M. Methods for the detection of autophagy in mammalian cells. Curr. Protoc. Toxicol., 2016, 69, 20.12.1-20.12.26..
Kung, C.P.; Budina, A.; Balaburski, G.; Bergenstock, M.K.; Murphy, M. Autophagy in tumor suppression and cancer therapy. Crit. Rev. Eukaryot. Gene Expr., 2011, 21(1), 71-100.
[] [PMID: 21967333]
Russo, M.; Russo, G.L. Autophagy inducers in cancer. Biochem. Pharmacol., 2018, 153, 51-61.
[] [PMID: 29438677]
Bhat, P.; Kriel, J.; Shubha Priya, B. Basappa.; Shivananju, N.S.; Loos, B. Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization. Biochem. Pharmacol., 2018, 147, 170-182.
[] [PMID: 29203368]
Zhang, X.; Schönrogge, M.; Eichberg, J.; Wendt, E.H.U.; Kumstel, S.; Stenzel, J.; Lindner, T.; Jaster, R.; Krause, B.J.; Vollmar, B.; Zechner, D. Blocking autophagy in cancer-associated fibroblasts supports chemotherapy of pancreatic cancer cells. Front. Oncol., 2018, 8(590), 590.
[] [PMID: 30568920]
Zinnah, K.M.A.; Park, S.Y. Duloxetine enhances TRAIL-mediated apoptosis via AMPK-mediated inhibition of autophagy flux in lung cancer cells. Anticancer Res., 2019, 39(12), 6621-6633.
[] [PMID: 31810927]
Qiao, X.; Wang, X.; Shang, Y.; Li, Y.; Chen, S. Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up-regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo. Cancer Commun., 2018, 38(1), 1-13.
[] [PMID: 29970185]
Mauthe, M.; Orhon, I.; Rocchi, C.; Zhou, X.; Luhr, M.; Hijlkema, K.J.; Coppes, R.P.; Engedal, N.; Mari, M.; Reggiori, F. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy, 2018, 14(8), 1435-1455.
[] [PMID: 29940786]
Levy, J.M.M.; Towers, C.G.; Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer, 2017, 17(9), 528-542.
[] [PMID: 28751651]
Onorati, A.V.; Dyczynski, M.; Ojha, R.; Amaravadi, R.K. Targeting autophagy in cancer. Cancer, 2018, 124(16), 3307-3318.
[] [PMID: 29671878]
Ostuzzi, G.; Matcham, F.; Dauchy, S.; Barbui, C.; Hotopf, M. Antidepressants for the treatment of depression in people with cancer. Cochrane Libr., 2018, 2018(4), CD011006-CD011006.
[] [PMID: 29683474]
Deng, L.; Lee, W.H.; Xu, Z.; Makriyannis, A.; Hohmann, A.G. Prophylactic treatment with the tricyclic antidepressant desipramine prevents development of paclitaxel-induced neuropathic pain through activation of endogenous analgesic systems. Pharmacol. Res., 2016, 114, 75-89.
[] [PMID: 27773824]
Lu, T.; Huang, C.C.; Lu, Y.C.; Lin, K.L.; Liu, S.I.; Wang, B.W.; Chang, P.M.; Chen, I.S.; Chen, S.S.; Tsai, J.Y.; Chou, C.T.; Jan, C.R. Desipramine-induced Ca2+ -independent apoptosis in MG63 human osteosarcoma cells: Dependence on P38 mitogen-activated protein kinase-regulated activation of caspase 3. Clin. Exp. Pharmacol. Physiol., 2009, 36(3), 297-303.
[] [PMID: 18986328]
Arimochi, H.; Morita, K. Desipramine induces apoptotic cell death through nonmitochondrial and mitochondrial pathways in different types of human colon carcinoma cells. Pharmacology, 2008, 81(2), 164-172.
[] [PMID: 18025841]
Chang, H.C.; Huang, C.C.; Huang, C.J.; Cheng, J.S.; Liu, S.I.; Tsai, J.Y.; Chang, H.T.; Huang, J.K.; Chou, C.T.; Jan, C.R. Desipramine-induced apoptosis in human PC3 prostate cancer cells: Activation of JNK kinase and caspase-3 pathways and a protective role of [Ca2+]i elevation. Toxicology, 2008, 250(1), 9-14.
[] [PMID: 18606486]
Ma, J.; Qiu, Y.; Yang, L.; Peng, L.; Xia, Z.; Hou, L.N.; Fang, C.; Qi, H.; Chen, H.Z. Desipramine induces apoptosis in rat glioma cells via endoplasmic reticulum stress-dependent CHOP pathway. J. Neurooncol., 2011, 101(1), 41-48.
[] [PMID: 20549303]
Kinjo, T.; Kowalczyk, P.; Kowalczyk, M.; Walaszek, Z.; Slaga, T.J.; Hanausek, M. Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells. Int. J. Mol. Med., 2010, 25(6), 861-867.
[PMID: 20428789]
Rasheduzzaman, M.; Park, S.Y. Antihypertensive drug-candesartan attenuates TRAIL resistance in human lung cancer via AMPK-mediated inhibition of autophagy flux. Exp. Cell Res., 2018, 368(1), 126-135.
[] [PMID: 29694835]
Nazim, U.M.; Park, S.Y. Genistein enhances TRAIL-induced cancer cell death via inactivation of autophagic flux. Oncol. Rep., 2015, 34(5), 2692-2698.
[] [PMID: 26352862]
Zinnah, K.; Park, S.Y. Sensitizing TRAIL resistant A549 lung cancer cells and enhancing TRAIL induced apoptosis with the antidepressant amitriptyline. Oncol. Rep., 2021, 46(1), 144.
[] [PMID: 34080659]
Zinnah, K.; Seol, J.W.; Park, S.Y. Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int. J. Mol. Med., 2020, 46(2), 795-805.
[] [PMID: 32626921]
Moon, J.H.; Park, S.Y. Prion peptide-mediated calcium level alteration governs neuronal cell damage through AMPK-autophagy flux. Cell Commun. Signal., 2020, 18(1), 109.
[] [PMID: 32650778]
Nazim, U.M.D.; Moon, J.H.; Lee, Y.J.; Seol, J.W.; Park, S.Y. PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget, 2017, 8(16), 26819-26831.
[] [PMID: 28460464]
Nazim, U.; Yin, H.; Park, S.Y. Neferine treatment enhances the TRAIL induced apoptosis of human prostate cancer cells via autophagic flux and the JNK pathway. Int. J. Oncol., 2020, 56(5), 1152-1161.
[] [PMID: 32319589]
Pimentel, J.M.; Zhou, J.Y.; Wu, G.S. The role of TRAIL in apoptosis and immunosurveillance in cancer. Cancers, 2023, 15(10), 2752.
[] [PMID: 37345089]
Artykov, A.A.; Belov, D.A.; Shipunova, V.O.; Trushina, D.B.; Deyev, S.M.; Dolgikh, D.A.; Kirpichnikov, M.P.; Gasparian, M.E. Chemotherapeutic agents sensitize resistant cancer cells to the DR5-specific variant DR5-B more efficiently than to TRAIL by modulating the surface expression of death and decoy receptors. Cancers, 2020, 12(5), 1129.
[] [PMID: 32365976]
Park, E.J.; Min, K.; Choi, K.S.; Kubatka, P.; Kruzliak, P.; Kim, D.E.; Kwon, T.K. Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells. Sci. Rep., 2016, 6(1), 22921.
[] [PMID: 26964637]
Smith, H.R. Depression in cancer patients: Pathogenesis, implications and treatment. (Review). Oncol. Lett., 2015, 9(4), 1509-1514.
[] [PMID: 25788991]
Gross, A.F.; Smith, F.A.; Stern, T.A. Is depression an appropriate response to having cancer? A discussion of diagnostic criteria and treatment decisions. Prim. Care Companion J. Clin. Psychiatry, 2007, 9(5), 382-387.
[] [PMID: 17998958]
Hartung, T.J.; Brähler, E.; Faller, H.; Härter, M.; Hinz, A.; Johansen, C.; Keller, M.; Koch, U.; Schulz, H.; Weis, J.; Mehnert, A. The risk of being depressed is significantly higher in cancer patients than in the general population: Prevalence and severity of depressive symptoms across major cancer types. Eur. J. Cancer, 2017, 72, 46-53.
[] [PMID: 28024266]
Alizadeh, Z. H.; Szegezdi, E. TRAIL in the treatment of cancer: From soluble cytokine to nanosystems. Cancers, 2022, 14(20), 5125.
[] [PMID: 36291908]
Mérino, D.; Lalaoui, N.; Morizot, A.; Solary, E.; Micheau, O. TRAIL in cancer therapy: Present and future challenges. Expert Opin. Ther. Targets, 2007, 11(10), 1299-1314.
[] [PMID: 17907960]
de Miguel, D.; Lemke, J.; Anel, A.; Walczak, H.; Martinez-Lostao, L. Onto better TRAILs for cancer treatment. Cell Death Differ., 2016, 23(5), 733-747.
[] [PMID: 26943322]
Lemke, J.; von Karstedt, S.; Zinngrebe, J.; Walczak, H. Getting TRAIL back on track for cancer therapy. Cell Death Differ., 2014, 21(9), 1350-1364.
[] [PMID: 24948009]
Ganley, I.G.; Wong, P.M.; Gammoh, N.; Jiang, X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell, 2011, 42(6), 731-743.
[] [PMID: 21700220]
Pugsley, H.R. Assessing autophagic flux by measuring LC3, p62, and LAMP1 co-localization using multispectral imaging flow cytometry. J. Vis. Exp., 2017, (125), 55637.
[PMID: 28784946]
Yang, Z.J.; Chee, C.E.; Huang, S.; Sinicrope, F.A. The role of autophagy in cancer: Therapeutic implications. Mol. Cancer Ther., 2011, 10(9), 1533-1541.
[] [PMID: 21878654]
Xu, Y.; Wang, Q.; Zhang, L.; Zheng, M. 2-Deoxy-d-glucose enhances TRAIL-induced apoptosis in human gastric cancer cells through downregulating JNK-mediated cytoprotective autophagy. Cancer Chemother. Pharmacol., 2018, 81(3), 555-564.
[] [PMID: 29383484]
Marinković, M.; Šprung, M.; Buljubašić, M.; Novak, I. Autophagy modulation in cancer: Current knowledge on action and therapy. Oxid. Med. Cell. Longev., 2018, 2018, 1-18.
[] [PMID: 29643976]
Mohsen, S.; Sobash, P.T.; Algwaiz, G.F.; Nasef, N.; Al-Zeidaneen, S.A.; Karim, N.A. Autophagy agents in clinical trials for cancer therapy: A brief review. Curr. Oncol., 2022, 29(3), 1695-1708.
[] [PMID: 35323341]
Fitzwalter, B.E.; Towers, C.G.; Sullivan, K.D.; Andrysik, Z.; Hoh, M.; Ludwig, M.; O’Prey, J.; Ryan, K.M.; Espinosa, J.M.; Morgan, M.J.; Thorburn, A. Autophagy inhibition mediates apoptosis sensitization in cancer therapy by relieving FOXO3a turnover. Dev. Cell, 2018, 44(5), 555-565.e3.
[] [PMID: 29533771]
Pan, H.; Wang, Y.; Na, K.; Wang, Y.; Wang, L.; Li, Z.; Guo, C.; Guo, D.; Wang, X. Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation. Cell Death Dis., 2019, 10(6), 456.
[] [PMID: 31186406]
Nazim, U.M.D.; Rasheduzzaman, M.; Lee, Y.J.; Seol, D.W.; Park, S.Y. Enhancement of TRAIL-induced apoptosis by 5-fluorouracil requires activating Bax and p53 pathways in TRAIL-resistant lung cancers. Oncotarget, 2017, 8(11), 18095-18105.
[] [PMID: 28178647]
Yoshii, S.R.; Mizushima, N. Monitoring and measuring autophagy. Int. J. Mol. Sci., 2017, 18(9), 1865.
[] [PMID: 28846632]

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