Assessment of In Vitro Cytotoxic Efficacy of Atypical Antidepressant Bupropion Hydrochloride in Glioma
Yıl 2025,
Cilt: 9 Sayı: 2, 215 - 219, 18.12.2025
Suna Karadeniz Saygılı
,
Ertan Katırcı
Öz
Bupropion hydrochloride (Wellbutrin; WB), an atypical antidepressant of the aminoketone class, is a selective norepinephrine and dopamine reuptake inhibitor used in the treatment of major depression. In this study, the potential effects of bupropion on brain cancer were investigated using rat C6 glioma cells. The cytotoxicity levels and IC50 values of bupropion were determined using the MTT method. Also, we analyzed caspase-3 immunoreactivity with immunofluorescence staining. Additionally, the effectiveness of the determined bupropion IC50 dose on colony development was assessed using a colony formation assay. It was found that bupropion had toxic activity on glioma cancer cells in direct proportion to the increase in applied doses. As a result of the immunocytochemical analysis performed on cells with IC50 value, it was found that the drug at the IC50 dose increased caspase-3 immunoreactivity in C6 cells compared to the control group. In addition, a decrease in the number of colonies was detected. Considering that bupropion increased apoptotic caspase-3 activation in C6 cells at the IC50 dose, elucidation of the molecular mechanisms behind these effects may contribute to the development of a new perspective in treatment.
Etik Beyan
This study did not require ethical approval as it was conducted solely on established cell lines and involved no human or animal subjects.
Kaynakça
-
Ascher, J.A., Cole, J.O., Colin, J.N., Feighner, J.P., Ferris, R.M., Fibiger, H.C., ... & Richelson, E. (1995). Bupropion: a review of its mechanism of antidepressant activity. The Journal of clinical psychiatry, 56(9), 395-401.
-
Bagó, J.R., Okolie, O., Dumitru, R., Ewend, M.G., Parker, J.S., Werff, R.V., ... & Hingtgen, S.D. (2017). Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Science translational medicine, 9(375), eaah6510. https://doi.org/10.1126/scitranslmed.aah6510
-
Bhattacharya, S.K., Nathawat, L.S., Damani, P., Choksi, A.K., Banik, A., Sinha, K., & Bhattacharya, A.S. (2013). Assessment of potential in vitro genotoxic and cytotoxic effects of bupropion hydrochloride (Wellbutrin) in human peripheral lymphocytes and human cortical neuron. Toxicology International, 20(1), 11. https://doi.org/10.4103/0971-6580.111535
-
Bilir, A., Erguven, M., Oktem, G., Ozdemir, A., Uslu, A., Aktas, E., & Bonavida, B. (2008). Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. International journal of oncology, 32(4), 829-839. https://doi.org/10.3892/ijo.32.4.829
-
Cortés, A., Cascante, M., Cárdenas, M.L., & Cornısh-Bowden, A. (2001). Relationships between inhibition constants, inhibitor concentrations for 50% inhibition and types of inhibition: new ways of analysing data. Biochemical Journal, 357(1), 263-268. https://doi.org/10.1042/bj3570263
-
Dikmen, M., Cantürk, Z., & Oztürk, Y. (2011). Escitalopram oxalate, a selective serotonin reuptake inhibitor, exhibits cytotoxic and apoptotic effects in glioma C6 cells. Acta Neuropsychiatrica, 23(4), 173–178. https://doi.org/10.1111/j.1601-5215.2011.00550.x
-
Jang, E.H., Park, C.S., & Kang, J.H. (2011). Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells. Toxicology, 285(1-2), 1–7. https://doi.org/10.1016/j.tox.2011.02.006
-
Jang, W.J., Jung, S.K., Vo, T.T.L., & Jeong, C.H. (2019). Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3. Journal of Cellular and Molecular Medicine, 23(2), 1106-1115. https://doi.org/10.1111/jcmm.14008
-
Kaya, I., Cingoz, I.D., Saygili, S.K., Ozyurt, R., & Sahin, M.C. (2023). Investigation of the anticancer effect of S-allyl-L cysteine on the C6 rat glioma cell line in vitro in 2D-and 3D-cell culture models. Turk Neurosurg, 33(5), 764-771. https://doi.org/10.5137/1019-5149.JTN.36033-21.3
-
Krebber, A.M.H., Buffart, L.M., Kleijn, G., Riepma, I.C., De Bree, R., Leemans, C.R., ... & Verdonck‐de Leeuw, I. (2014). Prevalence of depression in cancer patients: a meta‐analysis of diagnostic interviews and self‐report instruments. Psycho‐oncology, 23(2), 121-130. https://doi.org/10.1002/pon.3409
-
Levkovitz, Y., Gil-Ad, I., Zeldich, E., Dayag, M., & Weizman, A. (2005). Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for pc-Jun, cytochrome c, and caspase-3 involvement. Journal of Molecular Neuroscience, 27(1), 29-42. https://doi.org/10.1385/JMN:27:1:029
-
Liu, B., Zhou, H., Tan, L., Siu, K.T.H., & Guan, X.Y. (2024). Exploring treatment options in cancer: tumor treatment strategies. Signal Transduction and Targeted Therapy, 9(1), 175. https://doi.org/10.1038/s41392-024-01856-7
-
Ma, J., Yang, Y.R., Chen, W., Chen, M.H., Wang, H., Wang, X.D., ... & Wang, D.C. (2016). Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncology Reports, 36(2), 676-684. https://doi.org/10.3892/or.2016.4860
-
Mugge, L., Mansour, T.R., Crippen, M., Alam, Y., & Schroeder, J. (2020). Depression and glioblastoma, complicated concomitant diseases: a systemic review of published literature. Neurosurgical Review, 43(2), 497-511. https://doi.org/10.1007/s10143-018-09987-2
-
Nautiyal, K., Li, R., Yellapragada, S., Thiagarajan, P., Mims, M., & Rivero, G. (2015). Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor. Leukemia Research Reports, 4(1), 1-3. https://doi.org/10.1016/j.lrr.2014.03.001
-
Otto-Meyer, S., Lumibao, J., Kim, E., Ladomersky, E., Zhai, L., Lauing, K.L., ... & Wainwright, D.A. (2019). The interplay among psychological distress, the immune system, and brain tumor patient outcomes. Current Opinion in Behavioral Sciences, 28, 44-50. https://doi.org/10.1016/j.cobeha.2019.01.001
-
Pan, Z., Zeng, Y., Ye, Z., Li, Y., Wang, Y., Feng, Z., ... & Liu, X. (2024). Rotor-based image-guided therapy of glioblastoma. Journal of Controlled Release, 368, 650-662. https://doi.org/10.1016/j.jconrel.2024.03.020
-
Patel, K., Allen, S., Haque, M.N., Angelescu, I., Baumeister, D., & Tracy, D.K. (2016). Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Therapeutic Advances in Psychopharmacology, 6(2), 99-144. https://doi.org/10.1177/2045125316629071
-
Singh, S., Dey, D., Barik, D., Mohapatra, I., Kim, S., Sharma, M., ... & Singh, G. (2025). Glioblastoma at the crossroads: current understanding and future therapeutic horizons. Signal Transduction and Targeted Therapy, 10(1), 213. https://doi.org/10.1038/s41392-025-02299-4
-
van Tellingen, O., Yetkin-Arik, B., De Gooijer, M.C., Wesseling, P., Wurdinger, T., & De Vries, H.E. (2015). Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resistance Updates, 19, 1-12. https://doi.org/10.1016/j.drup.2015.02.002
-
Vasilev, A., Sofi, R., Tong, L., Teschemacher, A.G., & Kasparov, S. (2018). In search of a breakthrough therapy for glioblastoma multiforme. Neuroglia, 1(2), 292-310. https://doi.org/10.3390/neuroglia1020019
-
Xia, Z., DePierre, J.W., & Nässberger, L. (1998). Modulation of apoptosis induced by tricyclic antidepressants in human peripheral lymphocytes. Journal of Biochemical and Molecular Toxicology, 12(2), 115–123. https://doi.org/10.1002/(sici)1099-0461(1998)12:2<115::aid-jbt6>3.0.co;2-o
-
Yadavalli, S., Yenugonda, V.M., & Kesari, S. (2019). Repurposed Drugs in Treating Glioblastoma Multiforme: Clinical Trials Update. Cancer Journal (Sudbury, Mass.), 25(2), 139–146. https://doi.org/10.1097/PPO.0000000000000365
Glioma Hücrelerinde Atipik Antidepresan Bupropion Hidroklorürün in Vitro Sitotoksik Etkinliğinin Değerlendirilmesi
Yıl 2025,
Cilt: 9 Sayı: 2, 215 - 219, 18.12.2025
Suna Karadeniz Saygılı
,
Ertan Katırcı
Öz
Aminoketon sınıfından atipik bir antidepresan olan bupropion hidroklorür (Wellbutrin; WB), majör depresyon tedavisinde kullanılan seçici bir norepinefrin ve dopamin geri alım inhibitörüdür. Bu çalışmada, bupropionun beyin kanseri üzerindeki potansiyel etkileri rat C6 glioma hücreleri kullanılarak araştırılmıştır. Bupropionun sitotoksisite düzeyleri ve IC50 değerleri MTT yöntemi kullanılarak belirlenmiştir. Ayrıca, immünfloresan boyama ile kaspaz-3 immünoreaktivitesi analiz edilmiştir. Belirlenen bupropion IC50 dozunun koloni oluşturma üzerindeki etkinliğini tespit etmek için koloni oluşumu deneyi gerçekleştirilmiştir. Bupropionun uygulanan dozlardaki artışla doğru orantılı olarak glioma kanser hücreleri üzerinde toksik aktiviteye sahip olduğu bulunmuştur. IC50 değerinde bupropion uygulanan hücrelerde yapılan immünositokimyasal analiz sonucunda, ilacın IC50 dozunda C6 hücrelerinde kontrol grubuna kıyasla kaspaz-3 immünoreaktivitesini artırdığı bulunmuştur. Ayrıca koloni sayısında azalma tespit edilmiştir. Bupropionun IC50 dozunda C6 hücrelerinde apoptotik kaspaz-3 aktivasyonunu artırdığı göz önüne alındığında, bu etkilerin ardındaki moleküler mekanizmaların aydınlatılması, tedavide yeni bir bakış açısı geliştirilmesine katkı sağlayabilir.
Etik Beyan
Bu çalışma, yalnızca hücre kültürü üzerinde gerçekleştirildiğinden ve insan veya hayvan denek içermediğinden etik kurul onayı gerektirmemektedir.
Kaynakça
-
Ascher, J.A., Cole, J.O., Colin, J.N., Feighner, J.P., Ferris, R.M., Fibiger, H.C., ... & Richelson, E. (1995). Bupropion: a review of its mechanism of antidepressant activity. The Journal of clinical psychiatry, 56(9), 395-401.
-
Bagó, J.R., Okolie, O., Dumitru, R., Ewend, M.G., Parker, J.S., Werff, R.V., ... & Hingtgen, S.D. (2017). Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Science translational medicine, 9(375), eaah6510. https://doi.org/10.1126/scitranslmed.aah6510
-
Bhattacharya, S.K., Nathawat, L.S., Damani, P., Choksi, A.K., Banik, A., Sinha, K., & Bhattacharya, A.S. (2013). Assessment of potential in vitro genotoxic and cytotoxic effects of bupropion hydrochloride (Wellbutrin) in human peripheral lymphocytes and human cortical neuron. Toxicology International, 20(1), 11. https://doi.org/10.4103/0971-6580.111535
-
Bilir, A., Erguven, M., Oktem, G., Ozdemir, A., Uslu, A., Aktas, E., & Bonavida, B. (2008). Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma. International journal of oncology, 32(4), 829-839. https://doi.org/10.3892/ijo.32.4.829
-
Cortés, A., Cascante, M., Cárdenas, M.L., & Cornısh-Bowden, A. (2001). Relationships between inhibition constants, inhibitor concentrations for 50% inhibition and types of inhibition: new ways of analysing data. Biochemical Journal, 357(1), 263-268. https://doi.org/10.1042/bj3570263
-
Dikmen, M., Cantürk, Z., & Oztürk, Y. (2011). Escitalopram oxalate, a selective serotonin reuptake inhibitor, exhibits cytotoxic and apoptotic effects in glioma C6 cells. Acta Neuropsychiatrica, 23(4), 173–178. https://doi.org/10.1111/j.1601-5215.2011.00550.x
-
Jang, E.H., Park, C.S., & Kang, J.H. (2011). Bupropion, an atypical antidepressant, induces endoplasmic reticulum stress and caspase-dependent cytotoxicity in SH-SY5Y cells. Toxicology, 285(1-2), 1–7. https://doi.org/10.1016/j.tox.2011.02.006
-
Jang, W.J., Jung, S.K., Vo, T.T.L., & Jeong, C.H. (2019). Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3. Journal of Cellular and Molecular Medicine, 23(2), 1106-1115. https://doi.org/10.1111/jcmm.14008
-
Kaya, I., Cingoz, I.D., Saygili, S.K., Ozyurt, R., & Sahin, M.C. (2023). Investigation of the anticancer effect of S-allyl-L cysteine on the C6 rat glioma cell line in vitro in 2D-and 3D-cell culture models. Turk Neurosurg, 33(5), 764-771. https://doi.org/10.5137/1019-5149.JTN.36033-21.3
-
Krebber, A.M.H., Buffart, L.M., Kleijn, G., Riepma, I.C., De Bree, R., Leemans, C.R., ... & Verdonck‐de Leeuw, I. (2014). Prevalence of depression in cancer patients: a meta‐analysis of diagnostic interviews and self‐report instruments. Psycho‐oncology, 23(2), 121-130. https://doi.org/10.1002/pon.3409
-
Levkovitz, Y., Gil-Ad, I., Zeldich, E., Dayag, M., & Weizman, A. (2005). Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for pc-Jun, cytochrome c, and caspase-3 involvement. Journal of Molecular Neuroscience, 27(1), 29-42. https://doi.org/10.1385/JMN:27:1:029
-
Liu, B., Zhou, H., Tan, L., Siu, K.T.H., & Guan, X.Y. (2024). Exploring treatment options in cancer: tumor treatment strategies. Signal Transduction and Targeted Therapy, 9(1), 175. https://doi.org/10.1038/s41392-024-01856-7
-
Ma, J., Yang, Y.R., Chen, W., Chen, M.H., Wang, H., Wang, X.D., ... & Wang, D.C. (2016). Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncology Reports, 36(2), 676-684. https://doi.org/10.3892/or.2016.4860
-
Mugge, L., Mansour, T.R., Crippen, M., Alam, Y., & Schroeder, J. (2020). Depression and glioblastoma, complicated concomitant diseases: a systemic review of published literature. Neurosurgical Review, 43(2), 497-511. https://doi.org/10.1007/s10143-018-09987-2
-
Nautiyal, K., Li, R., Yellapragada, S., Thiagarajan, P., Mims, M., & Rivero, G. (2015). Progressive transfusion and growth factor independence with adjuvant sertraline in low risk myelodysplastic syndrome treated with an erythropoiesis stimulating agent and granulocyte-colony stimulating factor. Leukemia Research Reports, 4(1), 1-3. https://doi.org/10.1016/j.lrr.2014.03.001
-
Otto-Meyer, S., Lumibao, J., Kim, E., Ladomersky, E., Zhai, L., Lauing, K.L., ... & Wainwright, D.A. (2019). The interplay among psychological distress, the immune system, and brain tumor patient outcomes. Current Opinion in Behavioral Sciences, 28, 44-50. https://doi.org/10.1016/j.cobeha.2019.01.001
-
Pan, Z., Zeng, Y., Ye, Z., Li, Y., Wang, Y., Feng, Z., ... & Liu, X. (2024). Rotor-based image-guided therapy of glioblastoma. Journal of Controlled Release, 368, 650-662. https://doi.org/10.1016/j.jconrel.2024.03.020
-
Patel, K., Allen, S., Haque, M.N., Angelescu, I., Baumeister, D., & Tracy, D.K. (2016). Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Therapeutic Advances in Psychopharmacology, 6(2), 99-144. https://doi.org/10.1177/2045125316629071
-
Singh, S., Dey, D., Barik, D., Mohapatra, I., Kim, S., Sharma, M., ... & Singh, G. (2025). Glioblastoma at the crossroads: current understanding and future therapeutic horizons. Signal Transduction and Targeted Therapy, 10(1), 213. https://doi.org/10.1038/s41392-025-02299-4
-
van Tellingen, O., Yetkin-Arik, B., De Gooijer, M.C., Wesseling, P., Wurdinger, T., & De Vries, H.E. (2015). Overcoming the blood–brain tumor barrier for effective glioblastoma treatment. Drug Resistance Updates, 19, 1-12. https://doi.org/10.1016/j.drup.2015.02.002
-
Vasilev, A., Sofi, R., Tong, L., Teschemacher, A.G., & Kasparov, S. (2018). In search of a breakthrough therapy for glioblastoma multiforme. Neuroglia, 1(2), 292-310. https://doi.org/10.3390/neuroglia1020019
-
Xia, Z., DePierre, J.W., & Nässberger, L. (1998). Modulation of apoptosis induced by tricyclic antidepressants in human peripheral lymphocytes. Journal of Biochemical and Molecular Toxicology, 12(2), 115–123. https://doi.org/10.1002/(sici)1099-0461(1998)12:2<115::aid-jbt6>3.0.co;2-o
-
Yadavalli, S., Yenugonda, V.M., & Kesari, S. (2019). Repurposed Drugs in Treating Glioblastoma Multiforme: Clinical Trials Update. Cancer Journal (Sudbury, Mass.), 25(2), 139–146. https://doi.org/10.1097/PPO.0000000000000365