MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells

  • Authors:
    • Seon Hee Kim
    • Yong Jung Kang
    • Bokyung Sung
    • Dong Hwan Kim
    • Hyun Sook Lim
    • Hye Rim Kim
    • Seong Jin Kim
    • Jeong-Hyun Yoon
    • Hyung Ryong Moon
    • Hae Young Chung
    • Nam Deuk Kim
  • View Affiliations

  • Published online on: May 18, 2015     https://doi.org/10.3892/or.2015.3984
  • Pages: 288-294
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

MHY-449 is a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative designed and synthesized as a potential anticancer agent. The present study aimed to examine the anticancer activity and underlying mechanism of MHY-449. The cell viability assay performed in AGS human gastric carcinoma cells demonstrated that MHY-449 inhibited cell proliferation in a concentration-dependent manner. MHY-449 induced AGS cell death via apoptosis. The underlying molecular mechanism of MHY-449-mediated apoptosis was also investigated. MHY-449 promoted the upregulation of Fas and Fas-ligand, and activation of caspase-8, suggesting the involvement of a Fas-mediated extrinsic pathway in MHY-449-induced apoptosis. In addition, it was found that MHY-449-induced apoptosis was accompanied by the upregulation of Bax, p21WAF1/CIP1, p27KIP1, and p53 and suppression of Bcl-2. MHY-449 exposure activated the caspase cascade and subsequent poly(ADP‑ribose) polymerase (PARP) cleavage. Furthermore, the pan‑caspase inhibitor, Z-VAD-FMK, significantly attenuated MHY-449-induced apoptosis, indicating that the apoptosis was caspase-dependent. Moreover, the apoptogenic effect of MHY-449 was reactive oxygen species (ROS)-dependent. This result was confirmed by the induction of ROS by MHY-449 and by evidence that the scavenging of ROS by N-acetyl-L-cysteine inhibited MHY-449-induced cell death. Taken together, these results demonstrated that MHY-449 triggers apoptosis via caspase activation and ROS production. This result provides a novel mechanistic explanation and a basis for developing this compound as a novel candidate for human cancer therapy.
View Figures
View References

Related Articles

Journal Cover

July-2015
Volume 34 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Kim SH, Kang YJ, Sung B, Kim DH, Lim HS, Kim HR, Kim SJ, Yoon J, Moon HR, Chung HY, Chung HY, et al: MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells. Oncol Rep 34: 288-294, 2015
APA
Kim, S.H., Kang, Y.J., Sung, B., Kim, D.H., Lim, H.S., Kim, H.R. ... Kim, N.D. (2015). MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells. Oncology Reports, 34, 288-294. https://doi.org/10.3892/or.2015.3984
MLA
Kim, S. H., Kang, Y. J., Sung, B., Kim, D. H., Lim, H. S., Kim, H. R., Kim, S. J., Yoon, J., Moon, H. R., Chung, H. Y., Kim, N. D."MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells". Oncology Reports 34.1 (2015): 288-294.
Chicago
Kim, S. H., Kang, Y. J., Sung, B., Kim, D. H., Lim, H. S., Kim, H. R., Kim, S. J., Yoon, J., Moon, H. R., Chung, H. Y., Kim, N. D."MHY-449, a novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, mediates oxidative stress-induced apoptosis in AGS human gastric cancer cells". Oncology Reports 34, no. 1 (2015): 288-294. https://doi.org/10.3892/or.2015.3984