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Anticancer Activity of Bispidinone Derivative by Induction of Apoptosis

  • Lee, Man Gi (Department of Sports Healthcare, Inje University) ;
  • Kwon, Ryong (Department of Biomedicinal Chemistry, Inje University)
  • Received : 2020.10.29
  • Accepted : 2020.12.28
  • Published : 2020.12.31

Abstract

The present study was carried out to investigate the possibility that bispidinone derivative makes anticancer drug availability to human cervical carcinoma cell. The B8 has the lowest IC50 value among B8, B9 and B10 which are bispidinone analogue with bromide. According to cytotoxic test through WST-8 assay, B8 shows the most magnificent cytotoxicity effectiveness with 76 μM of IC50 value. In human cervical carcinoma cell treated with B8, it noticeably controlled cellular multiplication by increase of concentration and time. Furthermore, morphological changes like cellular shrink, disruption and nuclear condensation, feature of apoptosis, are observed. Annexin V-FITC/PI double staining assay test proved that B8 can cause apoptosis. Moreover, after treatment with 76 μM of B8, flow cytometry analysis shows that increase of active oxygen species are induced and membrane potential in mitochondria is decreased. Manifestation of Bcl-2 family and caspase cascades protein provides evidence that B8 induces apoptosis through mitochondria and caspase-related pathway. Taken together, we suggested that B8 reduced membrane potential in mitochondria and induce apoptosis through the pathway depended on mitochondria and caspase.

Keywords

References

  1. Aline MN, Amandine R, Maryame SY, Loic JC. 2,4-Substituted bispidines as rigid hosts for versatile applications: from kopioid receptor to metal coordination. Dalton Trans. 2019. 48: 16476-16492. https://doi.org/10.1039/C9DT03480C
  2. Chan WH, Wu CC, Yu JS. Curcumin inhibits UV irradiationinduced oxidative stress and apoptosis biochemical changes in human epidermoid carcinoma A431 cells. J of Cellular Biochem. 2003. 90: 327-338. https://doi.org/10.1002/jcb.10638
  3. Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie. 2002. 84: 131-141. https://doi.org/10.1016/S0300-9084(02)01369-X
  4. Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006. 25: 4798-4811. https://doi.org/10.1038/sj.onc.1209608
  5. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. C.A. Cancer J Clin. 2005. 55: 178-194. https://doi.org/10.3322/canjclin.55.3.178
  6. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999. 13: 1899-1911. https://doi.org/10.1101/gad.13.15.1899
  7. Jiang CP, et al. Pro-apoptotic effect of tectorigenin on human hepatocellular carcinoma HepG2 cells. World J Gastroenterol. 2012. 18: 1753-1764. https://doi.org/10.3748/wjg.v18.i15.1753
  8. Jaiprakash NS, Abhay SZ, Firoz AK, Indrajeet G, Zahid Z. Synthesis and biological activity of substituted-4,5,6,7-tetrahydrothieno pyridines: a review. Mini Rev Med Chem. 2014. 14: 988-1020. https://doi.org/10.2174/1389557514666141106131425
  9. Kiechle FL, Zhang X. Apoptosis: biochemical aspects and clinical implications. Clin Chim Acta. 2002. 326: 27-45. https://doi.org/10.1016/S0009-8981(02)00297-8
  10. Kraus W, Emmerling F, Comba P. Hexadentate bispidine derivatives as versatile bifunctional chelate agents for copper (II) radioisotopes. Bioconjug Chem. 2009. 20: 347-359. https://doi.org/10.1021/bc800461e
  11. LeBras M, Clement MV, Pervaiz S, Brenner C. Reactive oxygen species and the mitochondrial signaling pathway of cell death. Histol Histopathol. 2005. 20: 205-220.
  12. Limon HV, Hai-Yehia A, Levi-Schaffer F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 2000. 5: 415-418. https://doi.org/10.1023/a:1009616228304
  13. Lobrich M, Jeggo PA. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nature Reviews. 2007. 7: 861-869.
  14. Mine EI, Gunger K, Emine S. Antioxidant enzyme activities and malondialdehyde levels related to aging. Clinica Chimica Acta. 2001. 305: 75-80. https://doi.org/10.1016/S0009-8981(00)00422-8
  15. Murray A. Cell cycle checkpoints. Curr Opin Cell Biol. 1994. 6: 872-876. https://doi.org/10.1016/0955-0674(94)90059-0
  16. Otsuki Y, Li Z, Shibata MA. Apoptotic detection methods from Morphology to gene. Prog Histochem Cytochem. 2003. 38: 275-339. https://doi.org/10.1016/S0079-6336(03)80002-5
  17. Pathak S, Sharma C, Jayaram HN, Singh N. Apoptotic signaling induced by benzamide riboside an in vitro study. Mol Cell Biochem. 2009. 328: 67-73. https://doi.org/10.1007/s11010-009-0075-8
  18. Predebon MJ, Bond DR, Brzozowski J, Jankowski H, Deane F, Tarleton M, Shaw AA, McCluskey A, Bowyer MC, Weidenhofer J, Scarlett CJ. The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro. Molecules. 2019. 24: 524-539. https://doi.org/10.3390/molecules24030524
  19. Pucci B, Kasten M, Giordano A. Cell cycle and apoptosis. Neoplasia. 2000. 2: 291-299. https://doi.org/10.1038/sj/neo/7900101
  20. Saitoh M, Nagai K, Nakagawa K, Yamamura T, Yamamoto S, Nishizaki T. Adenosine induces apoptosis in the human gastric cancer cells via an intrinsic pathway relevant to activation of AMP-activated protein kinase. Biochem Pharmacol. 2004. 67: 2005-2011. https://doi.org/10.1016/j.bcp.2004.01.020
  21. Wang C, Youle RJ. The role of mitochondria in apoptosis. Ann Rev Genet. 2009. 43: 95-118. https://doi.org/10.1146/annurev-genet-102108-134850
  22. Ziegler DS, Kung AL. Therapeutic targeting of apoptosis pathways in cancer. Curr Opin Oncol. 2008. 20: 97-103. https://doi.org/10.1097/CCO.0b013e3282f310f6