Tabersonine Induces the Apoptosis of Human Hepatocellular Carcinoma In vitro and In vivo

  • Авторлар: Li X.1, Li X.2, Chen L.3, Deng Y.4, Zheng Z.5, Ming Y.6
  • Мекемелер:
    1. partment of Bioengineering and Biotechnology, Institute of Chemical Engineering, Huaqiao University
    2. Fujian Provincial Key Laboratory of new target drugs (Xiamen University), School of Pharmaceutical Sciences,, Xiamen University
    3. Key Laboratory of Fujian Province for Physiology and Biochemistry of Subtropical Plant,, Fujian Institute of Subtropical Botany
    4. Key Laboratory of Fujian Province for Physiology and Biochemistry of Subtropical Plant, Fujian Institute of Subtropical Botany,
    5. College of Life and Health Sciences,, Fuzhou Institute of Technology
    6. Department of Bioengineering and Biotechnology, Institute of Chemical Engineering,, Huaqiao University
  • Шығарылым: Том 24, № 10 (2024)
  • Беттер: 764-772
  • Бөлім: Oncology
  • URL: https://snv63.ru/1871-5206/article/view/643707
  • DOI: https://doi.org/10.2174/0118715206286612240303172230
  • ID: 643707

Дәйексөз келтіру

Толық мәтін

Аннотация

Background:Tabersonine, a natural indole alkaloid derived from Apocynaceae plants, exhibits antiinflammatory and acetylcholinesterase inhibitory activities, among other pharmacological effects. However, its anti-tumor properties and the underlying molecular mechanisms remain underexplored.

Objective:The present study aims to investigate the anti-tumor effects of tabersonine and its mechanisms in inducing apoptosis in hepatocellular carcinoma.

Methods:The inhibitory effects of tabersonine on the viability and proliferation of liver cancer cells were evaluated using MTT assay and colony formation assay. AO/EB, Hoechst, and Annexin V-FITC/ PI staining techniques were employed to observe cell damage and apoptosis. JC-1 staining was used to detect changes in mitochondrial membrane potential. Western blot analysis was conducted to study the anti-tumor mechanism of tabersonine on liver cancer cells. Additionally, a xenograft model using mice hepatoma HepG2 cells was established to assess the anti-tumor potency of tabersonine in vivo.

Results and Discussion:Our findings revealed that tabersonine significantly inhibited cell viability and proliferation, inducing apoptosis in liver cancer cells. Treatment with tabersonine inhibited Akt phosphorylation, reduced mitochondrial membrane potential, promoted cytochrome c release from mitochondria to the cytoplasm, and increased the ratio of Bax to Bcl-2. These findings suggested that tabersonine induces apoptosis in liver cancer cells through the mitochondrial pathway. Furthermore, tabersonine treatment activated the death receptor pathway of apoptosis. In vivo studies demonstrated that tabersonine significantly inhibited xenograft tumor growth.

Conclusion:Our study is the first to demonstrate that tabersonine induces apoptosis in HepG2 cells through both mitochondrial and death receptor apoptotic pathways, suggesting its potential as a therapeutic agent candidate for hepatic cancer.

Авторлар туралы

Xuan Li

partment of Bioengineering and Biotechnology, Institute of Chemical Engineering, Huaqiao University

Email: info@benthamscience.net

Xudan Li

Fujian Provincial Key Laboratory of new target drugs (Xiamen University), School of Pharmaceutical Sciences,, Xiamen University

Email: info@benthamscience.net

Lianghua Chen

Key Laboratory of Fujian Province for Physiology and Biochemistry of Subtropical Plant,, Fujian Institute of Subtropical Botany

Email: info@benthamscience.net

Yuan Deng

Key Laboratory of Fujian Province for Physiology and Biochemistry of Subtropical Plant, Fujian Institute of Subtropical Botany,

Email: info@benthamscience.net

Zhizhong Zheng

College of Life and Health Sciences,, Fuzhou Institute of Technology

Email: info@benthamscience.net

Yanlin Ming

Department of Bioengineering and Biotechnology, Institute of Chemical Engineering,, Huaqiao University

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Әдебиет тізімі

  1. El-Serag, H.B. Hepatocellular carcinoma. N. Engl. J. Med., 2011, 365(12), 1118-1127. doi: 10.1056/NEJMra1001683 PMID: 21992124
  2. Miamen, A.G.; Dong, H.; Roberts, L.R. Immunotherapeutic approaches to hepatocellular carcinoma treatment. Liver Cancer, 2012, 1(3-4), 226-237. doi: 10.1159/000343837 PMID: 24159587
  3. El-Serag, H.B.; Rudolph, K.L. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology, 2007, 132(7), 2557-2576. doi: 10.1053/j.gastro.2007.04.061 PMID: 17570226
  4. Zhong, C.; Li, Y.; Yang, J.; Jin, S.; Chen, G.; Li, D.; Fan, X.; Lin, H. Immunotherapy for hepatocellular carcinoma: Current limits and prospects. Front. Oncol., 2021, 11, 589680. doi: 10.3389/fonc.2021.589680 PMID: 33854960
  5. Kumari, R.; Sharma, A.; Ajay, A.K.; Bhat, M.K. Mitomycin C induces bystander killing in homogeneous and heterogeneous hepatoma cellular models. Mol. Cancer, 2009, 8(1), 87-87. doi: 10.1186/1476-4598-8-87 PMID: 19845939
  6. Tu, Y.; Zhu, S.; Wang, J.; Burstein, E.; Jia, D. Natural compounds in the chemoprevention of alcoholic liver disease. Phytother. Res., 2019, 33(9), 2192-2212. doi: 10.1002/ptr.6410 PMID: 31264302
  7. Kai, T.; Zhang, L.; Wang, X.; Jing, A.; Zhao, B.; Yu, X.; Zheng, J.; Zhou, F. Tabersonine inhibits amyloid fibril formation and cytotoxicity of Aβ(1-42). ACS Chem. Neurosci., 2015, 6(6), 879-888. doi: 10.1021/acschemneuro.5b00015 PMID: 25874995
  8. Morin, H.; Le Men, J.; Pourrat, H. Pharmacodynamic study of tabersonine, an alkaloid extracted from the seeds of Amsonia tabernaemontana Walt. (Apocyanaceae). Ann. Pharm. Fr., 1955, 13(2), 123-126. PMID: 14377161
  9. Qu, Y.; Safonova, O.; De Luca, V. Completion of the canonical pathway for assembly of anticancer drugs vincristine/vinblastine in Catharanthus roseus. Plant J., 2019, 97(2), 257-266. doi: 10.1111/tpj.14111 PMID: 30256480
  10. Dai, C.; Luo, W.; Chen, Y.; Shen, S.; Wang, Z.; Chen, R.; Wang, J.; Chattipakorn, N.; Huang, W.; Liang, G. Tabersonine attenuates Angiotensin II-induced cardiac remodeling and dysfunction through targeting TAK1 and inhibiting TAK1-mediated cardiac inflammation. Phytomedicine, 2022, 103, 154238. doi: 10.1016/j.phymed.2022.154238 PMID: 35696800
  11. Zhang, D.; Li, X.; Hu, Y.; Jiang, H.; Wu, Y.; Ding, Y.; Yu, K.; He, H.; Xu, J.; Sun, L.; Qian, F. Tabersonine attenuates lipopolysaccharide-induced acute lung injury via suppressing TRAF6 ubiquitination. Biochem. Pharmacol., 2018, 154, 183-192. doi: 10.1016/j.bcp.2018.05.004 PMID: 29746822
  12. Zhao, Q.; Zhu, W.T.; Ding, X.; Huo, Z.Q.; Donkor, P.O.; Adelakun, T.A.; Hao, X.J.; Zhang, Y. Voacafrines A-N, aspidosperma-type monoterpenoid indole alkaloids from Voacanga africana with AChE inhibitory activity. Phytochemistry, 2021, 181, 112566. doi: 10.1016/j.phytochem.2020.112566 PMID: 33197743
  13. Shi, S.; Song, L.; Liu, Y.; He, Y. Activation of CREB protein with tabersonine attenuates STAT3 during atherosclerosis in apolipoprotein E-deficient mice. Dose Response, 2020, 18(1), 1559325820912067. doi: 10.1177/1559325820912067 PMID: 32231468
  14. Sun, X.; Gan, L.; Li, N.; Sun, S.; Li, N. Tabersonine ameliorates osteoblast apoptosis in rats with dexamethasone-induced osteoporosis by regulating the Nrf2/ROS/Bax signalling pathway. AMB Express, 2020, 10(1), 165. doi: 10.1186/s13568-020-01098-0 PMID: 32915329
  15. Chuan, Y.; Wang, Y.; Jin, X.; Ming, S.; Bing, W.; Kai, W.; Xiang, C.; Kun, P. Activation of CREB-binding protein ameliorates spinal cord injury in tabersonine treatment by suppressing NLRP3/Notch signaling. Arch. Med. Sci., 2019, 19(3), 736-743. doi: 10.5114/aoms.2019.89203 PMID: 37313210
  16. Qu, Y.; Easson, M.L.A.E.; Froese, J.; Simionescu, R.; Hudlicky, T.; De Luca, V. Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. Proc. Natl. Acad. Sci. USA, 2015, 112(19), 6224-6229. doi: 10.1073/pnas.1501821112 PMID: 25918424
  17. Li, X.; Deng, Y.; Kang, L.; Chen, L.; Zheng, Z.; Huang, W.; Xu, C.; Kai, G.; Lin, D.; Tong, Q.; Lin, Y.; Ming, Y. Cytotoxic active ingredients from the seeds of Voacanga africana. S. Afr. J. Bot., 2021, 137, 311-319. doi: 10.1016/j.sajb.2020.10.028
  18. Ho, C.M.; Ho, S.L.; Shun, C.T.; Lee, P.H.; Chen, Y.H.; Chien, C.S.; Chen, H.L.; Hu, R.H. Histopathological evidence for the existence of primary liver progenitor cell cancer: Insight from cancer stem cell pathobiology. Discov. Med., 2017, 23(124), 41-50. PMID: 28245426
  19. Liu, C.Y.; Chen, K.F.; Chen, P.J. Treatment of liver cancer. Cold Spring Harb. Perspect. Med., 2015, 5(9), a021535. doi: 10.1101/cshperspect.a021535 PMID: 26187874
  20. Rawat, D.; Shrivastava, S.; Naik, R.A.; Chhonker, S.K.; Mehrotra, A.; Koiri, R.K. An overview of natural plant products in the treatment of hepatocellular carcinoma. Anticancer. Agents Med. Chem., 2019, 18(13), 1838-1859. doi: 10.2174/1871520618666180604085612 PMID: 29866017
  21. Liu, J.; He, Y.; Zhang, D.; Cai, Y.; Zhang, C.; Zhang, P.; Zhu, H.; Xu, N.; Liang, S. In vitro anticancer effects of two novel phenanthroindolizidine alkaloid compounds on human colon and liver cancer cells. Mol. Med. Rep., 2017, 16(3), 2595-2603. doi: 10.3892/mmr.2017.6879 PMID: 28677760
  22. Warren, C.F.A.; Wong-Brown, M.W.; Bowden, N.A. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis., 2019, 10(3), 177. doi: 10.1038/s41419-019-1407-6 PMID: 30792387
  23. Ehrenschwender, M.; Wajant, H. The role of FasL and Fas in health and disease. Adv. Exp. Med. Biol., 2009, 647(647), 64-93. doi: 10.1007/978-0-387-89520-8_5 PMID: 19760067
  24. Kaufmann, S.H.; Earnshaw, W.C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res., 2000, 256(1), 42-49. doi: 10.1006/excr.2000.4838 PMID: 10739650
  25. Hsieh, C.C.; Kuo, Y.H.; Kuo, C.C.; Chen, L.T.; Cheung, C.H.A.; Chao, T.Y.; Lin, C.H.; Pan, W.Y.; Chang, C.Y.; Chien, S.C.; Chen, T.W.; Lung, C.C.; Chang, J.Y.; Chamaecypanone, C. A novel skeleton microtubule inhibitor, with anticancer activity by trigger caspase 8-Fas/FasL dependent apoptotic pathway in human cancer cells. Biochem. Pharmacol., 2010, 79(9), 1261-1271. doi: 10.1016/j.bcp.2009.12.017 PMID: 20034474
  26. Henning, R.J.; Bourgeois, M.; Harbison, R.D. Poly(ADP-ribose) polymerase (PARP) and PARP inhibitors: Mechanisms of action and role in cardiovascular disorders. Cardiovasc. Toxicol., 2018, 18(6), 493-506. doi: 10.1007/s12012-018-9462-2 PMID: 29968072
  27. Chang, F.; Lee, J.T. Navolanic, PM Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia, 2003, 17(3), 590-603.
  28. Osaki, M.; Kase, S.; Adachi, K.; Takeda, A.; Hashimoto, K.; Ito, H. Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. J. Cancer Res. Clin. Oncol., 2004, 130(1), 8-14. doi: 10.1007/s00432-003-0505-z PMID: 14605879

Қосымша файлдар

Қосымша файлдар
Әрекет
1. JATS XML
Жүктеу

© Bentham Science Publishers, 2024