Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases

  • Authors:
    • Jung-Hyun Park
    • Eun-Jung Kim
    • Hye-Yeon Jang
    • Heyok Shim
    • Kang-Kyoo Lee
    • Hyang-Jeong Jo
    • Hwi-Jung Kim
    • Sei-Hoon Yang
    • Eun-Taik Jeong
    • Hak-Ryul Kim
  • View Affiliations

  • Published online on: Friday, August 1, 2008
  • Pages: 379-384 DOI: 10.3892/or_00000018

Abstract

Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.

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August 2008
Volume 20 Issue 2

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

2015 Impact Factor: 2.486
Ranked #31/211 Oncology
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APA
Park, J., Kim, E., Jang, H., Shim, H., Lee, K., Jo, H. ... Kim, H. (2008). Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases. Oncology Reports, 20, 379-384. http://dx.doi.org/10.3892/or_00000018
MLA
Park, J., Kim, E., Jang, H., Shim, H., Lee, K., Jo, H., Kim, H., Yang, S., Jeong, E., Kim, H."Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases". Oncology Reports 20.2 (2008): 379-384.
Chicago
Park, J., Kim, E., Jang, H., Shim, H., Lee, K., Jo, H., Kim, H., Yang, S., Jeong, E., Kim, H."Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases". Oncology Reports 20, no. 2 (2008): 379-384. http://dx.doi.org/10.3892/or_00000018