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A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS-mediated c-Abl/p38 MAPK signaling

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Abstract

Purpose

We investigated the action mechanism of a novel anticancer compound, KR28 (1-allyl-4-dodecanoyl-1-ethyl-piperazin-1-ium; bromide), to induce apoptosis of human prostate carcinoma PC-3 cells.

Methods

To explore an apoptotic signaling of KR28, we used ROS assay, SRB assay, flow cytometry analysis, reporter assay, xenograft assay, Western blotting, and RT-PCR analysis.

Results

The growth inhibitory action of KR28 is cell line specific, impeding the growth of prostate carcinoma PC-3 and stomach carcinoma NUGC-3 cells. KR28 showed strong antitumor activity in PC-3 mouse xenograft model. KR28 increased ROS production, leading to nuclear c-Abl expression, which in turn activated p38 mitogen-activated protein kinase (MAPK) to enhance the expression of RhoB, an apoptosis inducer. The KR28-induced apoptosis was abrogated by the ROS scavenger N-acetylcysteine and by knockdown of c-Abl, p38 MAPK, or ATF2. Moreover, the p300 binding site and two CCAAT boxes in the RhoB promoter appear to be involved in ROS-mediated RhoB expression in the presence of KR28.

Conclusion

The antitumor agent KR28 induces apoptosis of PC-3 cells by ROS-mediated RhoB expression via c-Abl upregulation and activation of p38 MAPK/ATF-2.

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Abbreviations

ROS:

Reactive oxygen species

NAC:

N-acetyl cysteine

MAPK:

Mitogen-activated protein kinase

SAPK/JNK:

Stress-activated protein kinase/c-Jun N-terminal kinase

PI3K:

Phosphoinositide 3-kinase

FTI:

Farnesyltransferase inhibitor

SRB:

Sulforhodamine B

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Acknowledgments

This work was supported in part by a grant from the 21st Century Frontier for Functional Analysis of the Human Genome (FG09-31-02), from the Ministry of Education, Science and Technology (2010-0025517, 2011-0007275), and the KRIBB Initiative.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Medical Genome Research Center, KRIBB, Yusong, Daejeon, 305-806, Korea

    Kyung-Sook Chung, Bo-Kyung Kim, Jiwon Ahn & Misun Won

  2. Functional Genomics, University of Science and Technology, Daejeon, 305-350, Korea

    Kyung-Sook Chung & Misun Won

  3. Department of Biotechnology, Yonsei University, Seoul, 129-749, Korea

    Gyoonhee Han & Jee Sun Yang

  4. College of Pharmacy, Gachon University, Incheon, 406-840, Korea

    Hwan-Mook Kim

  5. College of Pharmacy, Dongguk University, Gyeongju, Kyungki-do, 410-773, Korea

    Kyeong Lee

  6. Department of Food Science and Technology, Chungnam National University, Daejon, 305-764, Korea

    Kyung-Bin Song

Authors
  1. Kyung-Sook Chung
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  2. Gyoonhee Han
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  3. Bo-Kyung Kim
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  4. Hwan-Mook Kim
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  6. Jiwon Ahn
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  7. Kyeong Lee
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  8. Kyung-Bin Song
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  9. Misun Won
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Corresponding author

Correspondence to Misun Won.

Additional information

Kyung-Sook Chung, Gyoonhee Han and Bo-Kyung Kim have contributed equally to this work.

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Chung, KS., Han, G., Kim, BK. et al. A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS-mediated c-Abl/p38 MAPK signaling. Cancer Chemother Pharmacol 72, 1315–1324 (2013). https://doi.org/10.1007/s00280-013-2310-y

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  • DOI: https://doi.org/10.1007/s00280-013-2310-y

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