Sagantang-induced Apoptotic Cell Death is Associated with the Activation of Caspases in AGS Human Gastric Carcinoma Cells

사간탕 처리에 의한 AGS 인체 위암세포의 caspase 활성 의존적 apoptosis 유발

Park, Cheol;Hong, Su Hyun;Choi, Sung Hyun;Lee, Se-Ra;Leem, Sun-Hee;Choi, Yung Hyun

  • Received : 2015.07.27
  • Accepted : 2015.09.01
  • Published : 2015.12.30


Sagantang (SGT), a Korean multiherb formula comprising six medicinal herbs, Paeonia lactiflora Pall., Belamcanda chinensis (L.) DC, Gardenia jasminoides Ellis, Poria cocos Wolf, Cimicifuga heracleifolia Komarov, and Artractylodes japonica Koidzumi, was recorded in “Dongeuibogam.” The present study investigated the anticancer potential of SGT in AGS human gastric carcinoma cells. The results indicated that SGT treatment significantly inhibited the growth and viability of AGS cells in a dose-dependent manner, which was associated with the induction of apoptotic cell death, as evidenced by the formation of apoptotic bodies, in addition to chromatin condensation and DNA fragmentation, and the accumulation of annexin-V positive cells. The induction of apoptotic cell death by the SGT treatment was associated with up-regulation of Fas protein expression, truncation of Bid, and down-regulation of the anti-apoptotic Bcl-2 protein. The SGT treatment also effectively induced the loss of mitochondrial membrane potential, which was associated with the activation of caspases (caspase-3, -8, and -9) and degradation of poly (ADP-ribose) polymerase. However, a pan-caspase inhibitor significantly blocked the SGT-induced apoptosis and growth suppression in AGS cells. This study suggests that SGT induces caspase-dependent apoptosis through an extrinsic pathway by upregulating Fas, as well as through an intrinsic pathway by modulating Bcl-2 family members in AGS cells. The results suggest that SGT may be a potential chemotherapeutic agent for the control of human gastric cancer cells. However, further studies will be needed to confirm the potential of SGT in cancer prevention and therapy in an in vivo model and to identify biological active compounds of SGT.


AGS cells;apoptosis;caspase;mitochondrial membrane potential;Sagantang


  1. Jourdain, A. and Martinou, J. C. 2009. Mitochondrial outer-membrane permeabilization and remodelling in apoptosis. Int. J. Biochem. Cell Biol. 41, 1884-1889.
  2. Hong, M. H., Kim, J. H., Bae, H., Lee, N. Y., Shin, Y. C., Kim, S. H. and Ko, S. G. 2010. Atractylodes japonica Koidzumi inhibits the production of proinflammatory cytokines through inhibition of the NF-kappaB/IkappaB signal pathway in HMC-1 human mast cells. Arch. Pharm. Res. 33, 843-851.
  3. Hensley, P., Mishra, M. and Kyprianou, N. 2013. Targeting caspases in cancer therapeutics. Biol. Chem. 394, 831-843.
  4. Hassan, M., Watari, H., AbuAlmaaty, A., Ohba, Y. and Sakuragi, N. 2014. Apoptosis and molecular targeting therapy in cancer. Biomed. Res. Int. 2014, 150845.
  5. Fulda, S. and Debatin, K. M. 2006. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25, 4798-4811.
  6. Fiandalo, M. V. and Kyprianou, N. 2012. Caspase control: protagonists of cancer cell apoptosis. Exp. Oncol. 34, 165-175.
  7. Fennell, D. A. and Chacko, A. 2008. Exploiting BH3 only protein function for effective cancer therapy. Front Biosci. 13, 6682-6692.
  8. Eastman, A. 1995. Assays for DNA fragmentation, endonucleases, and intracellular pH and Ca2+ associated with apoptosis. Methods Cell Biol. 46, 41-55.
  9. Duriez, P. J. and Shah, G. M. 1997. Cleavage of poly (ADP-ribose) polymerase: a sensitive parameter to study cell death. Biochem. Cell Biol. 75, 337-349.
  10. Asakura, T. and Ohkawa, K. 2004. Chemotherapeutic agents that induce mitochondrial apoptosis. Curr. Cancer Drug Targets 4, 577-590.
  11. Park, H. and Kim, H. S. 2014. Korean traditional natural herbs and plants as immune enhancing, antidiabetic, chemopreventive, and antioxidative agents: a narrative review and perspective. J. Med. Food 17, 21-27.
  12. Ou, T. T., Wu, C. H., Hsu, J. D., Chyau, C. C., Lee, H. J., and Wang, C. J. 2011. Paeonia lactiflora Pall inhibits bladder cancer growth involving phosphorylation of Chk2 in vitro and in vivo. J. Ethnopharmacol. 135, 162-172.
  13. Ola, M. S., Nawaz, M. and Ahsan, H. 2011. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol. Cell. Biochem. 351, 41-58.
  14. Lee, J. H., Lee, D. U. and Jeong, C. S. 2009. Gardenia jasminoides Ellis ethanol extract and its constituents reduce the risks of gastritis and reverse gastric lesions in rats. Food Chem. Toxicol. 47, 1127-1131.
  15. Lavrik, I. N. 2010. Systems biology of apoptosis signaling networks. Curr. Opin. Biotechnol. 21, 551-555.
  16. Kyprianou, N., English, H. F. and Isaacs, J. T. 1998. Activation of a Ca2+-Mg2+-dependent endonuclease as an early event in castration-induced prostatic cell death. Prostate 13, 103-117.
  17. Kumar, H., Song, S. Y., More, S. V., Kang, S. M., Kim, B. W., Kim, I. S. and Choi, D. K. 2013. Traditional Korean east asian medicines and herbal formulations for cognitive impairment. Molecules 18, 14670-14693.
  18. Kasibhatla, S. and Tseng, B. 2003. Why target apoptosis in cancer treatment. Mol. Cancer Ther. 2, 573-580.
  19. Kadenbach, B., Arnold, S., Lee, I. and Hüttemann, M. 2004. The possible role of cytochrome c oxidase in stress-induced apoptosis and degenerative diseases. Biochim. Biophys. Acta. 1655, 400-4008.
  20. Zhang, W. and Dai, S. M. 2012. Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas in rheumatoid arthritis. Int. Immunopharmacol. 14, 27-31.
  21. Walczak, H. and Krammer, P. H. 2000. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp. Cell Res. 256, 58-66.
  22. Tomek, M., Akiyama, T. and Dass, C. R. 2012. Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy. J. Pharm. Pharmacol. 64, 1695-1702.
  23. Shamas-Din, A., Brahmbhatt, H., Leber, B. and Andrews, D. W. 2011. BH3-only proteins: Orchestrators of apoptosis. Biochim. Biophys. Acta. 1813, 508-520.
  24. Scorrano, L. and Korsmeyer, S. J. 2003. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304, 437-444.
  25. Ríos, J. L. 2011. Chemical constituents and pharmacological properties of Poria cocos. Planta Med. 77, 681-691.
  26. Park, S. J. and Kim, S. K. 2010. Anti-inflammatory Effects of Belamcanda chinensis Water Extract. Kor. J. Ori. Physiol. Pathol. 24, 410-415.
  27. Park, J., Shim, M., Rhyu, M. R. and Lee, Y. 2012. Estrogen receptor mediated effects of Cimicifuga extracts on human breast cancer cells. Pharmazie. 67, 947-950.