Investigation of the Cytotoxic Effect of Duloxetine Hydrochloride on DU-145 Human Prostate Cancer Cells

Yıl 2025, Cilt: 8 Sayı: 4, 132 - 138, 15.07.2025

Özge Kesgin , Serap Şahin

https://doi.org/10.19127/bshealthscience.1649481

Öz

Prostate cancer (PCa) is one of the most common cancers worldwide and accounts for a significant proportion of cancer-related deaths. Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), exerts an antidepressant role by inhibiting the reuptake of both norepinephrine and serotonin. There is no study on the cytotoxic effect of duloxetine hydrochloride on human prostate cancer cells (DU-145). In our study, the cytotoxic effects of duloxetine hydrochloride and cisplatin on DU-145 prostate cancer cells and healthy mouse fibroblast cells (L-929) were investigated using the 3-[4,5-Dimethylthiazol-2-Yl]-2,5-Diphenyl-Tetrazolium Bromide (MTT) assay. For cisplatin, the IC50 values for both DU-145 prostate cancer cells and L-929 healthy cell after 24-hour exposure were calculated as >50 µM. For duloxetine hydrochloride, the IC50 values after 24-hour exposure were calculated as 28.76 ± 0.012 µM for DU-145 cells and 34.92 ± 0.012 µM for L-929 cells. When duloxetine hydrochloride and cisplatin were applied together, the IC50 values were calculated as 30.51 ± 0.010 µM for DU-145 cells and 36.92 ± 0.013 µM for L-929 cells. A lower IC50 value indicates higher anticancer activity. Our results suggest that duloxetine hydrochloride exhibits higher cytotoxic activity against DU-145 cells compared to cisplatin. Additionally, the combined application of duloxetine hydrochloride and cisplatin showed a similar cytotoxic effect compared to that of the individual applications of cisplatin and duloxetine hydrochloride.

Anahtar Kelimeler

Duloxetine hydrochloride , Cell culture , Prostate cancer , Cytotoxicity , MTT

Proje Numarası

1919B012321409

Duloksetin Hidroklorür’ün DU-145 İnsan Prostat Kanser Hücreleri Üzerine Sitotoksik Etkisinin Araştırılması

Öz

Prostat kanseri (PKa), dünya çapında en yaygın kanserlerden birisi olup kansere bağlı ölümlerin büyük bir kısmını oluşturmaktadır. Bir serotonin-nöradrenalin geri alım inhibitörü (SNGI) olan duloksetin, hem norepinefrin hem de serotoninin geri alımının inhibisyonu yoluyla antidepresan bir rol oynamaktadır. Duloksetin hidroklorürün insan prostat kanser hücresi (DU-145) üzerine sitotoksik etkisi ile ilgili çalışma bulunmamaktadır. Çalışmamızda, duloksetin hidroklorür ve sisplatinin DU-145 prostat kanseri ve sağlıklı fare fibroblast hücreleri (L-929) üzerine sitotoksik etkileri 3-[4,5-Dimetiltiyazol-2-İl]-2,5-Difenil-Tetrazolyum Bromür (MTT) yöntemi ile araştırılmıştır. Sisplatinin hem DU-145 prostat kanser hücrelerinde hem de L-929 sağlıklı hücrelerde 24 saat uygulama süresi için IC50 değerleri; >50 µM olarak hesaplanmıştır. Duloksetin hidroklorürün 24 saat uygulama süresinde DU-145 ve L-929 hücreleri için IC50 değerleri sırasıyla; 28,76 ± 0,012 µM ve 34,92 ± 0,012 µM olarak hesaplanmıştır. Hücrelere, duloksetin hidroklorür ve sisplatinin birlikte uygulanması sonucunda IC50 değerleri; DU-145 hücre hattı için 30,51 ± 0,010 µM ve L-929 hücre hattı için 36,92 ± 0,013 µM olarak hesaplanmıştır. Düşük IC50 değeri yüksek antikanser aktiviteye işaret etmektedir. Sonuçlarımız DU-145 hücrelerine karşı, duloksetin hidroklorürün sisplatine göre daha yüksek sitotoksik etkinliğe sahip olduğunu, duloksetin hidroklorürün sisplatin ile birlikte uygulanmasının sisplatin ve duloksetin hidroklorürün ayrı ayrı uygulanması ile benzer sitotoksik etkinliğe sahip olduğunu göstermiştir.

Anahtar Kelimeler

Duloksetin hidroklorür , Hücre kültürü , Prostat kanseri , Sitotoksisite , MTT

Etik Beyan

Hayvanlar veya insanlar üzerinde bir çalışma olmadığı için bu çalışma için etik komite onayı gerekmemiştir.

Destekleyen Kurum

TÜBİTAK–Bilim İnsanı Destek Programları Başkanlığı (BİDEB)

Proje Numarası

1919B012321409

Teşekkür

Bu çalışma, TÜBİTAK–Bilim İnsanı Destek Programları Başkanlığı (BİDEB) 2209-A Üniversite Öğrencileri Araştırma Projeleri Destekleme Programı kapsamında ‘’1919B012321409’’ proje numarası ile desteklenmiştir.

Kaynakça

• Alvano SA, Zieher LM. 2020. An updated classification of antidepressants: A proposal to simplify treatment. Person Medic Psychiat, 19: 100042.
• Bailly C, Qu X, Chaires JB, Colson P, Houssier C, Ohkubo M, Yoshinari T. 1999. Substitution at the F-ring N-imide of the indolocarbazole antitumor drug NB-506 increases the cytotoxicity, DNA binding, and topoisomerase I inhibition activities. J Medic Chem, 42(15): 2927-2935.
• Bavadekar S, Panchal P, Hanbashi A, Vansal S. 2014. Cytotoxic effects of selective serotonin‐and serotonin‐norepinephrine reuptake inhibitors on human metastatic breast cancer cell line, MCF‐7 (842.3). FASEB J, 28: 842-843.
• Berrouet C, Dorilas N, Rejniak KA, Tuncer N. 2020. Comparison of drug inhibitory effects (IC 50) in monolayer and spheroid cultures. Bull Math Biol, 82(6): 68.
• Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Wong DT. 2001. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology, 25(6): 871-880.
• Ćwiklińska-Jurkowska M, Wiese-Szadkowska M, Janciauskiene S, Paprocka R. 2023. Disparities in cisplatin-ınduced cytotoxicity—A meta-analysis of selected cancer cell lines. Molecules, 28(15): 5761.
• Dasari S, Tchounwou PB. 2014. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol, 740: 364-378.
• Genç S, Soysal Mİ. 2018. Parametric and nonparametric post hoc tests. BSJ Eng Sci, 1(1): 18-27.
• Hager S, Ackermann CJ, Joerger M, Gillessen S, Omlin A. 2016. Anti-tumour activity of platinum compounds in advanced prostate cancer—A systematic literature review. Annals Oncol, 27(6): 975-984.
• Hassani M, Ghassemi-Barghi N, Modanloo M, Mohammadpour A, Shokrzadeh M. 2019. Cytotoxic effects of duloxetine on MKN45 and NIH3T3 cell lines and genotoxic effects on human peripheral blood lymphocytes. Arquivos de Gastroenterol, 56(4): 372-376.
• Hill BT, Whelan RD, Shellard SA, McClean S, Hosking LK. 1994. Differential cytotoxic effects of docetaxel in a range of mammalian tumor cell lines and certain drug resistant sublines in vitro. Invest New Drugs, 12: 169-182.
• Huang J, Zhao D, Liu Z, Liu F. 2018. Repurposing psychiatric drugs as anti-cancer agents. Cancer Lett, 419: 257-265.
• Jahchan NS, Dudley JT, Mazur PK, Flores N, Yang D, Palmerton A, Sage J. 2013. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov, 3(12): 1364-1377.
• Jang SK, Kim G, Ahn SH, Hong J, Jin HO, Park IC. 2024. Duloxetine enhances the sensitivity of non-small cell lung cancer cells to EGFR inhibitors by REDD1-induced mTORC1/S6K1 suppression. Amer J Cancer Res, 14(3): 1087.
• Kajiwara I, Sano M, Ichimaru Y, Oshima Y, Kitajima O, Hao H, Suzuki T. 2020. Duloxetine improves cancer-associated pain in a mouse model of pancreatic cancer through stimulation of noradrenaline pathway and its antitumor effects. Pain, 161(12): 2909-2919.
• Kim G, Jang SK, Ahn SH, Kim S, Park CS, Seong MK, Park IC. 2024. Proapoptotic role of CDK1 in overcoming paclitaxel resistance in ovarian cancer cells in response to combined treatment with paclitaxel and duloxetine. Cancer Cell Int, 24(1): 409.
• Kuwahara J, Yamada T, Egashira N, Ueda M, Zukeyama N, Ushio S, Masuda S. 2015. Comparison of the anti-tumor effects of selective serotonin reuptake inhibitors as well as serotonin and norepinephrine reuptake inhibitors in human hepatocellular carcinoma cells. Biol Pharmaceut Bull, 38(9): 1410-1414.
• Lazarova I, Nilofar Caprioli G, Piatti D, Ricciutelli M, Ulusan MD, Zengin G. 2024. Influence of extraction solvents on the chemical constituents and biological activities of Astragalus aduncus from Turkey flora: In vitro and in silico insights. Archiv der Pharmazie, 357(9): 2400257.
• Li QQ, Wang G, Reed E, Huang L, Cuff CF. 2010. Evaluation of Cisplatin in Combination with β‐Elemene as a Regimen for Prostate Cancer Chemotherapy. Basic Clin Pharmacol Toxicol, 107(5): 868-876.
• Meyer CT, Wooten DJ, Paudel BB, Bauer J, Hardeman KN, Westover D, Quaranta V. 2019. Quantifying drug combination synergy along potency and efficacy axes. Cell Syst, 8: 97-108.
• Pergolizzi Jr JV, Raffa RB, Taylor Jr R, Rodriguez G, Nalamachu S, Langley P. 2013. A review of duloxetine 60 mg once‐daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain. Pain Pract, 13(3): 239-252.
• Pula G, Pistilli A, Montagnoli C, Stabile AM, Rambotti MG, Rende M. 2013. The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75NTR-dependent apoptosis. Anti-cancer Drugs, 24(9): 899-910.
• Rottenberg S, Disler C, Perego P. 2021. The rediscovery of platinum-based cancer therapy. Nature Rev Cancer, 21(1): 37-50.
• Sagara A, Nakata K, Matsumoto S, Guan W, Shinkawa T, Iwamoto C, Nakamura M. 2021. Repositioning of duloxetine to target pancreatic stellate cells. Oncology Lett, 22(4): 744.
• Shao QS, Ye ZY, Ling ZQ, Ke JJ. 2005. Cell cycle arrest and apoptotic cell death in cultured human gastric carcinoma cells mediated by arsenic trioxide. World J Gastroenterol, 11(22): 3451.
• Sheffler ZM, Patel P, Abdijadid S. 2025. Antidepressants. URL: https://www.ncbi.nlm.nih.gov/books/NBK538182 (erişim tarihi: 26 Mayıs 2023).
• Stopper H, Garcia SB, Waaga-Gasser AM, Kannen V. 2014. Antidepressant fluoxetine and its potential against colon tumors. World J Gastrointest Oncol, 6(1): 11.
• Torre LA, Siegel RL, Ward EM, Jemal A. 2016. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomar Prevent, 25(1): 16-27.
• Vizcarra-Ramos S, Molina-Pineda A, Gutiérrez-Ortega A, Herrera-Rodríguez SE, Aguilar-Lemarroy A, Jave-Suárez LF, Hernández-Gutiérrez R. 2024. Synergistic Strategies in prostate cancer therapy: electrochemotherapy and electromagnetic hyperthermia. Pharmaceutics, 16(9): 1109.
• WHO. 2022. URL: https://gco.iarc.fr/today/en/dataviz/ pie?mode=cancer&group_populations (Erişim tarihi: 21 Şubat 2025).
• Yoo HW, Suh ME, Park SW. 1998. Synthesis and Cytotoxicity of 2-Methyl-4, 9-dihydro-1-substituted-1 H-imidazo [4, 5-g] quinoxaline-4, 9-diones and 2, 3-Disubstituted-5, 10-pyrazino [2, 3-g] quinoxalinediones. J Medicin Chem, 41(24): 4716-4722.
• Yuan SY, Cheng CL, Ho HC, Wang SS, Chiu KY, Su CK, Lin CC. 2015. Nortriptyline induces mitochondria and death receptor-mediated apoptosis in bladder cancer cells and inhibits bladder tumor growth in vivo. Eur J Pharmacol, 761: 309-320.
• Zhang Z, Du X, Zhao C, Cao B, Zhao Y, Mao X. 2013. The antidepressant amitriptyline shows potent therapeutic activity against multiple myeloma. Anti-cancer Drugs, 24(8): 792-798.
• Zheng Y, Chang X, Huang Y, He D. 2023. The application of antidepressant drugs in cancer treatment. Biomedic Pharmacother, 157: 113985.
• Zhu W, Li Y, Gao L. 2015. Cisplatin in combination with programmed cell death protein 5 increases antitumor activity in prostate cancer cells by promoting apoptosis. Molec Medic Rep, 11(6): 4561-4566.