Abstract
Glioma is an extremely aggressive primary brain tumor, which is highly resistant to chemotherapy, presenting a therapeutic challenge. Here, we explored the anti-glioma effects and the underlying mechanism of lycorine, an isoquinoline alkaloid isolated from lycoris on glioma cells. We found that lycorine could dose dependently inhibit C6 glioma cell growth and induce cell apoptosis and intracellular reactive oxygen species (ROS) production. The half-maximal inhibitory concentration (IC50) values of lycorine on C6 glioma cells at 48 h was 2.85 μM. Meanwhile, lycorine treatment caused dysfunction of the NF-κB signal, as demonstrated by the up-regulation of NF-κB inhibitor protein IκB and the downregulation of the NF-κB phosphorylation protein p-p65. The addition of NF-κB inhibitor SC75741 further confirmed the importance of the NF-κB pathway in lycorine-induced cell-growth inhibition. Moreover, lycorine might act synergically with temozolomide (TMZ) to reduce drug resistance by blocking the NF-κB pathway. Our study suggested that lycorine exerts an anti-glioma effect by inducing ROS production and inhibiting NF-κB, which validated that lycorine may be a potential candidate for glioma treatment alone or in combination with TMZ.
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All the data of this study are transparent and available upon request.
References
Bulusu KC, Guha R, Mason DJ, Lewis RP, Muratov E, KalantarMotamedi Y, Cokol M, Bender A (2016) Modelling of compound combination effects and applications to efficacy and toxicity: state-of-the-art, challenges and perspectives. Drug Discov Today 21:225–38
Cahill KE, Morshed RA, Yamini B (2016) Nuclear factor-kappaB in glioblastoma: insights into regulators and targeted therapy. Neuro Oncol 18:329–339
Ding L, Jiang P, Xu X, Lu W, Yang C, Zhou P, Liu S (2020) Resveratrol promotes HSV-2 replication by increasing histone acetylation and activating NF-kappaB. Biochem Pharmacol 171:113691
Goodenberger ML, Jenkins RB (2012) Genetics of Adult Glioma. Cancer Genet 205:613–621
Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J, N.C. Consortium (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443–9
Harris IS, DeNicola GM (2020) The complex interplay between antioxidants and ROS in cancer. Trends Cell Biol 30:440–451
Hu M, Yu Z, Mei P, Li J, Luo D, Zhang H, Zhou M, Liang F, Chen R (2020) Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging 12:138–155
Jalili-Nik M, Sadeghi MM, Mohtashami E, Mollazadeh H, Afshari AR, Sahebkar A (2020) Zerumbone promotes cytotoxicity in human malignant glioblastoma cells through reactive oxygen species (ROS) generation. Oxid Med Cell Longev 2020:3237983
Li C, Deng C, Pan G, Wang X, Zhang K, Dong Z, Zhao G, Tan M, Hu X, Shi S, Du J, Ji H, Wang X, Yang L, Cui H (2020) Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer. J Exp Clin Cancer Res 39:230
Liu WY, Tang Q, Zhang Q, Hu CP, Huang JB, Sheng FF, Liu YL, Zhou M, Lai WJ, Li GB, Zhang R (2019) Lycorine induces mitochondria-dependent apoptosis in hepatoblastoma HepG2 cells through ROCK1 activation. Front Pharmacol 10:651
Mendoza CA, Yamaoka S, Tsuda Y, Matsuno K, Weisend CM, Ebihara H (2021) The NF-kappaB inhibitor, SC75741, is a novel antiviral against emerging tick-borne bandaviruses. Antiviral Res 185:104993
Nasser MI, Masood M, Wei W, Li X, Zhou Y, Liu B, Li J, Li X (2017) Cordycepin induces apoptosis in SGC7901 cells through mitochondrial extrinsic phosphorylation of PI3K/Akt by generating ROS. Int J Oncol 50:911–919
Puliyappadamba VT, Hatanpaa KJ, Chakraborty S, Habib AA (2014) The role of NF-kappaB in the pathogenesis of glioma. Mol Cell Oncol 1:e963478
Roy M, Liang L, Xiao X, Peng Y, Luo Y, Zhou W, Zhang J, Qiu L, Zhang S, Liu F, Ye M, Zhou W, Liu J (2016) Lycorine downregulates HMGB1 to Inhibit autophagy and enhances bortezomib activity in multiple myeloma. Theranostics 6:2209–2224
Schimmel K, Jung M, Foinquinos A, Jose GS, Beaumont J, Bock K, Grote-Levi L, Xiao K, Bar C, Pfanne A, Just A, Zimmer K, Ngoy S, Lopez B, Ravassa S, Samolovac S, Janssen-Peters H, Remke J, Scherf K, Dangwal S, Piccoli MT, Kleemiss F, Kreutzer FP, Kenneweg F, Leonardy J, Hobuss L, Santer L, Do QT, Geffers R, Braesen JH, Schmitz J, Brandenberger C, Muller DN, Wilck N, Kaever V, Bahre H, Batkai S, Fiedler J, Alexander KM, Wertheim BM, Fisch S, Liao R, Diez J, Gonzalez A, Thum T (2020) Natural compound library screening identifies new molecules for the treatment of cardiac fibrosis and diastolic dysfunction. Circulation 141:751–767
Shen J, Zhang T, Cheng Z, Zhu N, Wang H, Lin L, Wang Z, Yi H, Hu M (2018) Lycorine inhibits glioblastoma multiforme growth through EGFR suppression. J Exp Clin Cancer Res 37:157
Silginer M, Weller M, Stupp R, Roth P (2017) Biological activity of tumor-treating fields in preclinical glioma models. Cell Death Dis 8:e2753
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, R. European Organisation for, T. Treatment of Cancer Brain, G. Radiotherapy, G. National Cancer Institute of Canada Clinical Trials (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–96
Volmar MNM, Cheng J, Alenezi H, Richter S, Haug A, Hassan Z, Goldberg M, Li Y, Hou M, Herold-Mende C, Maire CL, Lamszus K, Fluh C, Held-Feindt J, Gargiulo G, Topping GJ, Schilling F, Saur D, Schneider G, Synowitz M, Schick JA, Kalin RE, Glass R (2021) Cannabidiol converts NF-kappaB into a tumor suppressor in glioblastoma with defined antioxidative properties. Neuro Oncol 23:1898–1910
Wang Y, Qi H, Liu Y, Duan C, Liu X, Xia T, Chen D, Piao HL, Liu HX (2021) The double-edged roles of ROS in cancer prevention and therapy. Theranostics 11:4839–4857
Wu S, Qiu Y, Shao Y, Yin S, Wang R, Pang X, Ma J, Zhang C, Wu B, Koo S, Han L, Zhang Y, Gao X, Wang T, Yu H (2018) Lycorine Displays potent antitumor efficacy in colon carcinoma by targeting STAT3. Front Pharmacol 9:881
Zhang SY, Li XB, Hou SG, Sun Y, Shi YR, Lin SS (2016) Cedrol induces autophagy and apoptotic cell death in A549 non-small cell lung carcinoma cells through the P13K/Akt signaling pathway, the loss of mitochondrial transmembrane potential and the generation of ROS. Int J Mol Med 38:291–299
Zhang P, Zhang M, Yu D, Liu W, Hu L, Zhang B, Zhou Q, Cao Z (2019) Lycorine inhibits melanoma cell migration and metastasis mainly through reducing intracellular levels of beta-catenin and matrix metallopeptidase 9. J Cell Physiol 234:10566–10575
Zhang W, Yang J, Chen Y, Xue R, Mao Z, Lu W, Jiang Y (2021) Lycorine hydrochloride suppresses stress-induced premature cellular senescence by stabilizing the genome of human cells. Aging Cell 20:e13307
Funding
This work was funded by the Scientific Research Project of the Education Department of Hubei Province (Q20212805) and the Initial Scientific Research Fund of Ph.D. in Hubei University of Science and Technology (BK202120).
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All authors contributed to the study’s conception and design. Material preparation, experiment operation, data collection, and analysis were performed by WY, JS, and MMH. The first draft of the manuscript was written by QY and LQD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Su, J., Yin, W., Huo, M. et al. Induction of apoptosis in glioma cells by lycorine via reactive oxygen species generation and regulation of NF-κB pathways. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1247–1255 (2023). https://doi.org/10.1007/s00210-023-02384-x
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DOI: https://doi.org/10.1007/s00210-023-02384-x