Anti-cancer Potentials of Rhus verniciflua Stokes, Ulmus davidiana var. japonica Nakai and Arsenium Sublimatum in Human Gastric Cancer AGS Cells

AGS 인체위암세포에서 건칠, 유근피 및 신석 추출물의 항암 활성 비교 연구

  • Received : 2015.06.07
  • Accepted : 2015.08.03
  • Published : 2015.08.30


The anti-cancer activities of Rhus verniciflua Stokes (GC), Ulmus davidiana var. japonica Nakai (UGP) and arsenium sublimatum (SS) extracts, which have been used Oriental medicine therapy for various diseases, were investigated. The treatment of GC, UGP and SS alone, and combined treatment with GC, UGP and SS did not affect the cell viability in the mouse normal cell lines (RAW 264.7 macrophages and C2C12 myoblasts). However, co-treatment with GC, UGP and SS markedly induces apoptosis in human gastric cancer AGS cells, but not in other various cancer cell lines (human lung cancer A549, colon cancer HCT116, liver cancer Hep3B and bladder T24 cells) as evidenced by formation of apoptotic bodies, chromatin condensation, and accumulation of annexin-V positive cells. Co-treatment with GC, UGP and SS effectively induced the expression levels of Fas and Fas ligand, and inhibited the levels IAP family proteins such as XIAP, cIAP-1 and survivin, and anti-apoptotic Bcl-xL proteins compared with treatment with either agent alone. Combined treatment also significantly induced the loss of mitochondrial membrane potential, which was associated with the activation of caspases (-3, -8, and -9) and degradation of poly (ADP-ribose) polymerase. However, the cytotoxic effects induced by co-treatment with GC, UGP and SS were significantly attenuated by pan-caspases inhibitor, z-VAD-fmk, indicating an important role for caspases. These results indicated that the caspases were key regulators of apoptosis in response to co-treatment of GC, UGP and SS in human gastric cancer AGS cells and further studies will be needed to identify the active compounds.


Arsenium sublimatum;apoptosis;caspases;Rhus verniciflua Stokes;Ulmus davidiana var. japonica Nakai


  1. Peták, I. and Houghton, J. A. 2001. Shared pathways: death receptors and cytotoxic drugs in cancer therapy. Pathol. Oncol. Res. 7, 95-106.
  2. Roy, M. J., Vom, A., Czabotar, P. E. and Lessene, G. 2014. Cell death and the mitochondria: therapeutic targeting of the BCL-2 family-driven pathway. Br. J. Pharmacol. 171, 1973-1987.
  3. Roy, N., Deveraux, Q. L., Takahashi, R., Salvesen, G. S. and Reed, J. C. 1997. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16, 6914-6925.
  4. Shen, Z. X., Chen, G. Q., Ni, J. H., Li, X. S., Xiong, S. M., Qiu, Q. Y., Zhu, J., Tang, W., Sun, G. L., Yang, K. Q., Chen, Y., Zhou, L., Fang, Z. W., Wang, Y. T., Ma, J., Zhang, P., Zhang, T. D., Chen, S. J., Chen, Z. and Wang, Z. Y. 1997. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokineticsin relapsed patients. Blood 89, 3354-3360.
  5. Song, I. K., Kim, K. S., Suh, S. J., Kim, M. S., Kwon, D. Y., Kim, S. L. and Kim, C. H. 2007. Anti-inflammatory effect of Ulmus davidiana Planch (Ulmaceae) on collagen-induced inflammation in rats. Environ. Toxicol. Pharmacol. 23, 102-110.
  6. Soriano, M. E. and Scorrano, L. 2010. The interplay between BCL-2 family proteins and mitochondrial morphology in the regulation of apoptosis. Adv. Exp. Med. Biol. 687, 97-114.
  7. van Delft, M. F. and Huang, D. C. 2006. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res. 16, 203-213.
  8. Lee, U. D., Suh, S. J., Kim, K. S., Kim, D. S., Jin, U. H., Lee, I. S., Yoon, U. H. and Kim, C. H. 2007. Immunomodulatory activity of Ulmus davidiana Planch (Ulmaceae) water and ethanolic extracts on bone cells: Stimulation of proliferation, alkaline phosphatase activity and type I collagen synthesis. Environ. Toxicol. Pharmacol. 23, 154-161.
  9. Lee, J. C., Kim, J., Lim, K. T., Yang, M. S. and Jang, Y. S. 2001. Ethanol-eluted extract of Rhus verniciflua Stokes showed both antioxidant and cytotoxic effects on mouse thymocytes depending on the dose and time of the treatment. J. Biochem. Mol. Biol. 34, 250-258.
  10. Martinou, J. C. and Youle, R. J. 2011. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev. Cell 21, 92-101.
  11. Mita, A. C., Mita, M. M., Nawrocki, S. T. and Giles, F, J. 2008. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin. Cancer Res. 14, 5000-5005.
  12. Niu, C., Yan, H., Yu, T., Sun, H. P., Liu, J. X., Li, X. S., Wu, W., Zhang, F. Q., Chen, Y., Zhou, L., Li, J. M., Zeng, X. Y., Yang, R. R., Yuan, M. M., Ren, M. Y., Gu, F. Y., Cao, Q., Gu, B. W., Su, X. Y., Chen, G. Q., Xiong, S. M., Zhang, T. D., Waxman, S., Wang, Z. Y., Chen, Z., Hu, J., Shen, Z. X. and Chen, S. J. 1999. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94, 3315-3324.
  13. Okada, H. and Mak, T. W. 2004. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat. Rev. Cancer 4, 592-603.
  14. 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.
  15. Jung, H. J., Jeon, H. J., Lim, E. J., Ahn, E. K., Song, Y. S., Lee, S., Shin, K. H., Lim, C. J. and Park, E. H. 2007. Anti-angiogenic activity of the methanol extract and its fractions of Ulmus davidiana var. japonica. J. Ethnopharmacol. 112, 406-409.
  16. Jung, C. H., Jun, C. Y., Lee, S., Park, C. H., Cho, K. and Ko, S. G. 2006. Rhus verniciflua stokes extract: radical scavenging activities and protective effects on H2O2-induced cytotoxicity in macrophage RAW 264.7 cell lines. Biol. Pharm. Bull. 29, 1603-1607.
  17. Kim, J. P., Kim, W. G., Koshino, H., Jung, J. and Yoo, I. D. 1996. Sesquiterpene O-naphthoquinones from the root bark of Ulmus davidiana. Phytochemistry 43, 425-430.
  18. Kimberley, F. C. and Screaton, G. R. 2004. Following a TRAIL: update on a ligand and its five receptors. Cell Res. 14, 359-372.
  19. Kitt, D. D. and Lim, K. T. 2001. Antitumorigenic and cytotoxic properties of an ethanol extract derived from Rhus verniciflua Stokes (RVS). J. Toxicol. Environ. Health A 64, 357-371.
  20. Ko, J. H., Lee, S. J. and Lim, K. T. 2005. 116 kDa glycoprotein isolated from Ulmus davidiana Nakai (UDN) inhibits glucose/glucose oxidase (G/GO)-induced apoptosis in BNL CL.2 cells. J. Ethnopharmacol. 100, 339-346.
  21. Lee, J. C., Lee, K. Y., Son, Y. O., Choi, K. C., Kim, J., Truong, T. T. and Jang, Y. S. 2005. Plant-originated glycoprotein, G-120, inhibits the growth of MCF-7 cells and induces their apoptosis. Food Chem. Toxicol. 43, 961-968.
  22. Lee, J. H., Kim, M., Chang, K. H., Hong, C. Y., Na, C. S., Dong, M. S., Lee, D. and Lee, M. Y. 2015. Antiplatelet effects of Rhus verniciflua stokes heartwood and its active constituents-fisetin, butein, and sulfuretin-in rats. J. Med. Food 18, 21-30.
  23. Grzybowska-Izydorczyk, O. and Smolewski, P. 2008. The role of the inhibitor of apoptosis protein (IAP) family in hematological malignancies. Postepy Hig. Med. Dosw. 62, 55-63.
  24. Guidry, J. J., Greisinger, A., Aday, L. A., Winn, R. J., Vernon, S. and Throckmorton, T. A. 1996. Barriers to cancer treatment: a review of published research. Oncol. Nurs. Forum. 23, 1393-1398.
  25. Han, M. H., Lee, W. S., Lu, J. N., Yun, J. W., Kim, G., Jung, J. M., Kim, G. Y., Lee, S. J., Kim, W. J. and Choi, Y. H. 2012. Tetraarsenic hexoxide induces Beclin-1-induced autophagic cell death as well as caspase-dependent apoptosis in U937 human leukemic cells. Evid. Based Complement. Alternat. Med. 2012, 201414.
  26. Han, S. I., Kim, Y. S. and Kim, T. H. 2008. Role of apoptotic and necrotic cell death under physiologic conditions. BMB Rep. 41, 1-10.
  27. Hébert-Croteau, N., Freeman, C. R., Latreille, J. and Brisson, J. 2002. Delay in adjuvant radiation treatment and outcomes of breast cancer-a review. Breast Cancer Res. Treat. 74, 77-94.
  28. Hotchkiss, R. S. and Nicholson, D. W. 2006. Apoptosis and caspases regulate death and inflammation in sepsis. Nat. Rev. Immunol. 6, 813-822.
  29. Huerta, S., Goulet, E. J. and Livingston, E. H. 2006. Colon cancer and apoptosis. Am. J. Surg. 191, 517-526.
  30. Jin, U. H., Lee, D. Y., Kim, D. S., Lee, I. S. and Kim, C. H. 2006. Induction of mitochondria-mediated apoptosis by methanol fraction of Ulmus davidiana Planch (Ulmaceae) in U87 glioblastoma cells. Environ. Toxicol. Pharmacol. 22, 136-141.
  31. Jin, Z. and El-Deiry, W. S. 2005. Overview of cell death signaling pathways. Cancer Biol. Ther. 4, 139-163.
  32. Ahn, J., Lee, J. S. and Yang, K. M. 2014. Ultrafine particles of Ulmus davidiana var. japonica induce apoptosis of gastric cancer cells via activation of caspase and endoplasmic reticulum stress. Arch. Pharm. Res. 37, 783-792.
  33. Chen, S. Y., Li, X. M. and Liu, S. X. 2000. A review of the research on malignant hemopathies treated with arsenium-containing Chinese drugs. Zhongguo Zhong Yao Za Zhi 25, 454-457.
  34. Deveraux, Q. L. and Reed, J. C. 1999. IAP family proteins-suppressors of apoptosis. Genes Dev. 13, 239-252.
  35. Devi, G. R. 2004. XIAP as target for therapeutic apoptosis in prostate cancer. Drug News Perspect. 17, 127-134.
  36. Earnshaw, W. C., Martins, L. M. and Kaufmann, S. H. 1999. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383-424.

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