Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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6-Gingerol Induced Apoptosis and Cell Cycle Arrest in Glioma Cells via MnSOD and ERK Phosphorylation Modulation

  • Sher-Wei Lim (Department of Neurosurgery, Chi-Mei Medical Center) ;
  • Wei-Chung Chen (Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital) ;
  • Huey-Jiun Ko (Department of Biochemistry, College of Medicine, Kaohsiung Medical University) ;
  • Yu-Feng Su (Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital) ;
  • Chieh-Hsin Wu (Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital) ;
  • Fu-Long Huang (Department of Food Nutrition, Chung Hwa University of Medical Technology) ;
  • Chien-Feng Li (Department of Pathology, Chi-Mei Medical Center) ;
  • Cheng Yu Tsai (Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital)
  • Received : 2024.05.27
  • Accepted : 2024.09.27
  • Published : 2025.01.01
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Abstract

6-gingerol, a bioactive compound from ginger, has demonstrated promising anticancer properties across various cancer models by inducing apoptosis and inhibiting cell proliferation and invasion. In this study, we explore its mechanisms against glioblastoma multiforme (GBM), a notably aggressive and treatment-resistant brain tumor. We found that 6-gingerol crosses the blood-brain barrier more effectively than curcumin, enhancing its potential as a therapeutic agent for brain tumors. Our experiments show that 6-gingerol reduces cell proliferation and triggers apoptosis in GBM cell lines by disrupting cellular energy homeostasis. This process involves an increase in mitochondrial reactive oxygen species (mtROS) and a decrease in mitochondrial membrane potential, primarily due to the downregulation of manganese superoxide dismutase (MnSOD). Additionally, 6-gingerol reduces ERK phosphorylation by inhibiting EGFR and RAF, leading to G1 phase cell cycle arrest. These findings indicate that 6-gingerol promotes cell death in GBM cells by modulating MnSOD and ROS levels and arresting the cell cycle through the ERFR-RAF-1/MEK/ERK signaling pathway, highlighting its potential as a therapeutic agent for GBM and setting the stage for future clinical research.

Keywords

Acknowledgement

This research was supported by grants MOST-111-2314-B-037-095-MY2 (C.-Y.T.). The present research was supported by a grant from the Chi-Mei Medical Center and Kaohsiung Medical University Research Foundation (112CM-KMU-08) (C.-Y.T.), grants KMUH111-1T02 from Kaohsiung Medical University hospital (C.-Y.T.) and grants CCFHR11302 from ChiMei Medical Center (S.-W.L.).

References

  1. Afshari, A. R., Sanati, M., Kesharwani, P. and Sahebkar, A. (2023) Recent advances in curcumin-based combination nanomedicines for cancer therapy. J. Funct. Biomater. 14, 408.
  2. Ahmed, S. H. H., Gonda, T., Agbadua, O. G., Girst, G., Berkecz, R., Kúsz, N., Tsai, M. C., Wu, C. C., Balogh, G. T. and Hunyadi, A. (2023) Preparation and evaluation of 6-gingerol derivatives as novel antioxidants and antiplatelet agents. Antioxidants (Basel) 12, 744.
  3. Aloliqi, A. A. (2022) Therapeutic potential of 6-gingerol in prevention of colon cancer induced by azoxymethane through the modulation of antioxidant potential and inflammation. Curr. Issues Mol. Biol. 44, 6218-6228.
  4. Buccarelli, M., D'Alessandris, Q. G., Matarrese, P., Mollinari, C., Signore, M., Cappannini, A., Martini, M., D'Aliberti, P., De Luca, G., Pedini, F., Boe, A., Biffoni, M., Pallini, R. and Ricci-Vitiani, L. (2021) Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. J. Exp. Clin. Cancer Res. 40, 228.
  5. Czarnik-Kwaśniak, J., Kwaśniak, K., Kwasek, P., Świerzowska, E., Strojewska, A. and Tabarkiewicz, J. (2019) The influence of lycopene, [6]-gingerol, and silymarin on the apoptosis on U-118MG glioblastoma cells in vitro model. Nutrients 12, 96.
  6. de Lima, R. M. T., dos Reis, A. C., de Oliveira Santos, J. V., de Oliveira Ferreira, J. R., de Oliveira Filho, J. W. G., Soares Dias, A. C., de Menezes, A.-A. P. M., da Mata, A. M. O. F., de Alencar, M. V. O. B., de Jesus Aguiar dos Santos Andrade, T., Jardim Paz, M. F. C., do Nascimento Rodrigues, D. C., Ferreira, P. M. P., de Castro e Sousa, J. M., Mishra, S. K., Islam, M. T. and de Carvalho Melo-Cavalcante, A. A. (2020) Antitumoral effects of [6]-gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] in sar coma 180 cells through cytogenetic mechanisms. Biomed. Pharmacother. 126, 110004.
  7. Delello Di Filippo, L., Hofstätter Azambuja, J., Paes Dutra, J. A., Tavares Luiz, M., Lobato Duarte, J., Nicoleti, L. R., Olalla Saad, S. T. and Chorilli, M. (2021) Improving temozolomide biopharmaceutical properties in glioblastoma multiforme (GBM) treatment using GBM-targeting nanocarriers. Eur. J. Pharm. Biopharm. 168, 76-89.
  8. Dugasani, S., Pichika, M. R., Nadarajah, V. D., Balijepalli, M. K., Tandra, S. and Korlakunta, J. N. (2010) Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J. Ethnopharmacol. 127, 515-520.
  9. Eren, D. and Betul, Y. M. (2016) Revealing the effect of 6-gingerol, 6-shogaol and curcumin on mPGES-1, GSK-3β and β-catenin pathway in A549 cell line. Chem. Biol. Interact. 258, 257-265.
  10. Garnett, M. J. and Marais, R. (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313-319.
  11. Hart, P. C., Mao, M., de Abreu, A. L., Ansenberger-Fricano, K., Ekoue, D. N., Ganini, D., Kajdacsy-Balla, A., Diamond, A. M., Minshall, R. D., Consolaro, M. E., Santos, J. H. and Bonini, M. G. (2015) Mn-SOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat. Commun. 6, 6053.
  12. Hung, J. Y., Hsu, Y. L., Li, C. T., Ko, Y. C., Ni, W. C., Huang, M. S. and Kuo, P. L. (2009) 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J. Agric. Food Chem. 57, 9809-9816.
  13. Izadi, A., Sadeghi, A., Jalili-Nik, M., Mirzavi, F., Afshari, A. R. and Soukhtanloo, M. (2023) Combination of alpha-lipoic acid and auraptene induces apoptosis and prevents proliferation of the human U-87 glioblastoma cells. Rev. Bras. Farmacogn. 33, 1177-1186.
  14. Jiang, X., Wang, J., Chen, P., He, Z., Xu, J., Chen, Y., Liu, X. and Jiang, J. (2021) [6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling. Cancer Cell Int. 21, 420.
  15. Kamarajugadda, S., Cai, Q., Chen,H., Nayak, S., Zhu,J., He, M.,Jin, Y., Zhang, Y.,Ai, L., Martin, S.S., Tan, M. and Lu,J. (2013) Manganese superoxide dismutase promotes anoikis resistance and tumor metastasis. Cell Death Dis. 4, e504.
  16. Koustas, E., Karamouzis, M. V., Mihailidou, C., Schizas, D. and Papavassiliou, A. G. (2017) Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer. Cancer Lett. 396, 94-102.
  17. Lee, D. H., Kim, D. W., Jung, C. H., Lee, Y. J. and Park, D. (2014) Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. Toxicol. Appl. Pharmacol. 279, 253-265.
  18. Li, J., Feng, L. and Lu, Y. (2022) Glioblastoma multiforme: diagnosis, treatment, and invasion. J. Biomed. Res. 37, 47-58.
  19. Li, Z., Shi, K., Guan, L., Cao, T., Jiang, Q., Yang, Y. and Xu, C. (2010) ROS leads to MnSOD upregulation through ERK2 translocation and p53 activation in selenite-induced apoptosis of NB4 cells. FEBS Lett. 584, 2291-2297.
  20. Liu, C. M., An, L., Wu, Z., Ouyang, A. J., Su, M., Shao, Z., Lin, Y., Liu, X. and Jiang, Y. (2022) 6-Gingerol suppresses cell viability, migration and invasion via inhibiting EMT, and inducing autophagy and ferroptosis in LPS-stimulated and LPS-unstimulated prostate cancer cells. Oncol. Lett. 23, 187.
  21. Liu, H., Wang, L., Lv, M., Pei, R., Li, P., Pei, Z., Wang, Y., Su, W. and Xie, X. Q. (2014) AlzPlatform: an Alzheimer's disease domain-specific chemogenomics knowledgebase for polypharmacology and target identification research. J. Chem. Inf. Model. 54, 1050-1060.
  22. Lo, H. W. (2010a) EGFR-targeted therapy in malignant glioma: novel aspects and mechanisms of drug resistance. Curr. Mol. Pharmacol. 3, 37-52.
  23. Lo, H. W. (2010b) Nuclear mode of the EGFR signaling network: biology, prognostic value, and therapeutic implications. Discov. Med. 10, 44-51.
  24. Louis, D. N., Perry, A., Reifenberger, G., von Deimling, A., Figarella-Branger, D., Cavenee, W. K., Ohgaki, H., Wiestler, O. D., Kleihues, P. and Ellison, D. W. (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803-820.
  25. Manju, V. and Nalini, N. (2005) Chemopreventive efficacy of ginger, a naturally occurring anticarcinogen during the initiation, post-initiation stages of 1,2 dimethylhydrazine-induced colon cancer. Clin. Chim. Acta 358, 60-67.
  26. McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W. T., Chang, F., Lehmann, B., Terrian, D. M., Milella, M., Tafuri, A., Stivala, F., Libra, M., Basecke, J., Evangelisti, C., Martelli, A. M. and Franklin, R. A. (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 1773, 1263-1284.
  27. Miller, C. R. and Perry, A. (2007) Glioblastoma. Arch. Pathol. Lab. Med. 131, 397-406.
  28. Oberley, L. W. (2005) Mechanism of the tumor suppressive effect of MnSOD overexpression. Biomed. Pharmacother. 59, 143-148.
  29. Pandey, N., Anastasiadis, P., Carney, C. P., Kanvinde, P. P., Woodworth, G. F., Winkles, J. A. and Kim, A. J. (2022) Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment. Adv. Drug Deliv. Rev. 188, 114415.
  30. Park, J. K., Hodges, T., Arko, L., Shen, M., Dello Iacono, D., McNabb, A., Olsen Bailey, N., Kreisl, T. N., Iwamoto, F. M., Sul, J., Auh, S., Park, G. E., Fine, H. A. and Black, P. M. (2010) Scale to predict survival after surgery for recurrent glioblastoma multiforme. J. Clin. Oncol. 28, 3838-3843.
  31. Promdam, N. and Panichayupakaranant, P. (2022) [6]-Gingerol: a narrative review of its beneficial effect on human health. Food Chem. Adv. 1, 100043.
  32. Qi, L. W., Zhang, Z., Zhang, C. F., Anderson, S., Liu, Q., Yuan, C. S. and Wang, C. Z. (2015) Anti-colon cancer effects of 6-shogaol through G2/M cell cycle arrest by p53/p21-cdc2/cdc25A crosstalk. Am. J. Chin. Med. 43, 743-756.
  33. Robb, E. L. and Stuart, J. A. (2010) trans-Resveratrol as a neuroprotectant. Molecules 15, 1196-1212.
  34. Roshan, M. K., Afshari, A. R., Mirzavi, F., Mousavi, S. H. and Soukhtanloo, M. (2023) Combretastatin A-4 suppresses the invasive and metastatic behavior of glioma cells and induces apoptosis in them: in-vitro study. Med. Oncol. 40, 331.
  35. Roskoski, R., Jr. (2018) Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol. Res. 135, 239-258.
  36. Salari, Z., Khosravi, A., Pourkhandani, E., Molaakbari, E., Salarkia, E., Keyhani, A., Sharifi, I., Tavakkoli, H., Sohbati, S., Dabiri, S., Ren, G. and Shafie'ei, M. (2023) The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity: in silico, in vitro, and in vivo. Front. Oncol. 13, 1098429.
  37. Sanati, M., Binabaj, M. M., Ahmadi, S. S., Aminyavari, S., Javid, H., Mollazadeh, H., Bibak, B., Mohtashami, E., Jamialahmadi, T., Afshari, A. R. and Sahebkar, A. (2022) Recent advances in glioblastoma multiforme therapy: a focus on autophagy regulation. Biomed. Pharmacother. 155, 113740.
  38. Saxena, N., Lahiri, S. S., Hambarde, S. and Tripathi, R. P. (2008) RAS: target for cancer therapy. Cancer Invest. 26, 948-955.
  39. Simon, A., Darcsi, A., Kéry, Á. and Riethmüller, E. (2020) Blood-brain barrier permeability study of ginger constituents. J. Pharm. Biomed. Anal. 177, 112820.
  40. Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y. and Wei, X. (2023) Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: current status in clinical trials. Genes Dis. 10, 76-88.
  41. Sp, N., Kang, D. Y., Lee, J. M., Bae, S. W. and Jang, K. J. (2021) Potential antitumor effects of 6-gingerol in p53-dependent mitochondrial apoptosis and inhibition of tumor sphere formation in breast cancer cells. Int. J. Mol. Sci. 22, 4660.
  42. Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., Belanger, K., Brandes, A. A., Marosi, C., Bogdahn, U., Curschmann, J., Janzer, R. C., Ludwin, S. K., Gorlia, T., Allgeier, A., Lacombe, D., Cairncross, J. G., Eisenhauer, E. and Mirimanoff, R. O. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987-996.
  43. Tang, H., Shao, C., Wang, X., Cao, Y., Li, Z., Luo, X., Yang, X. and Zhang, Y. (2022) 6-Gingerol attenuates subarachnoid hemorrhage-induced early brain injury via GBP2/PI3K/AKT pathway in the rat model. Front. Pharmacol. 13, 882121.
  44. Tarin, M., Babaie, M., Eshghi, H., Matin, M. M. and Saljooghi, A. S. (2023) Elesclomol, a copper-transporting therapeutic agent targeting mitochondria: from discovery to its novel applications. J. Transl. Med. 21, 745.
  45. Tong, S., Xia, M., Xu, Y., Sun, Q., Ye, L., Yuan, F., Wang, Y., Cai, J., Ye, Z. and Tian, D. (2023) Identification and validation of a novel prognostic signature based on mitochondria and oxidative stress related genes for glioblastoma. J. Transl. Med. 21, 136.
  46. Tsai, C. Y., Ko, H. J., Huang, C. F., Lin, C. Y., Chiou, S. J., Su, Y. F., Lieu, A. S., Loh, J. K., Kwan, A. L., Chuang, T. H. and Hong, Y. R. (2021) Ionizing radiation induces resistant glioblastoma stem-like cells by promoting autophagy via the Wnt/β-catenin pathway. Life (Basel) 11, 451.
  47. Tsai, Y., Xia, C. and Sun, Z. (2020) The inhibitory effect of 6-gingerol on ubiquitin-specific peptidase 14 enhances autophagy-dependent ferroptosis and anti-tumor in vivo and in vitro. Front. Pharmacol. 11, 598555.
  48. Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T. D., Mazur, M. and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44-84.
  49. Weng, C. J., Chou, C. P., Ho, C. T. and Yen, G. C. (2012) Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Mol. Nutr. Food Res. 56, 1304-1314.
  50. Wu, D., Liu, Z., Li, J., Zhang, Q., Zhong, P., Teng, T., Chen, M., Xie, Z., Ji, A. and Li, Y. (2019) Epigallocatechin-3-gallate inhibits the growth and increases the apoptosis of human thyroid carcinoma cells through suppression of EGFR/RAS/RAF/MEK/ERK signaling pathway. Cancer Cell Int. 19, 43.
  51. Xing, M. (2013) Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer 13, 184-199.
  52. Yuan, L., Wang, J., Xiao, H., Wu, W., Wang, Y. and Liu, X. (2013) MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells. Food Chem. Toxicol. 53, 62-68.
  53. Zhang, H., Kim, E., Yi, J., Hai, H., Kim, H., Park, S., Lim, S. G., Kim, S. Y., Jang, S., Kim, K., Kim, E. K., Lee, Y., Ryoo, Z. and Kim, M. (2021) [6]-Gingerol suppresses oral cancer cell growth by inducing the activation of AMPK and suppressing the AKT/mTOR signaling pathway. In Vivo 35, 3193-3201.
  54. Zhong, W., Oberley, L. W., Oberley, T. D. and Clair, D. K. S. (1997) Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene 14, 481-490.