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Arsenic trioxide prevents radiation-enhanced tumor invasiveness and inhibits matrix metalloproteinase-9 through downregulation of nuclear factor κB

Oncogene volume 24, pages 390–398 (2005)Cite this article

Abstract

Arsenic trioxide (ATO) has been implicated as a promising anticancer agent by inhibiting cell growth and inducing apoptosis in certain types of cancer cells. This study explored the antimetastasis property of arsenic, drew potential link between arsenic use and radiotherapy, and uncovered the specific mechanisms underlying these remarkable responses. Using gelatin invasion assay and intravasation assay, we report the novel finding that low-dose ATO (1 μ M) reduced the intrinsic migration ability of HeLa cells and significantly inhibited radiation-promoted tumor invasive potential of CaSki cells without inducing apoptotic cell death. Using the murine Lewis lung carcinoma model, the control animals and ATO treatment animals (1 mg/kg i.p., twice weekly) displayed similar in vivo growth kinetics, whereas the radiation (30 Gy in one fraction) and concurrent treatment groups showed considerable growth inhibition. Importantly, although concurrent treatment did not enhance the effectiveness of radiation therapy to the primary tumor, further examination of the lungs revealed that all animals succumbed to radiation-accelerated lung metastases could be effectively treated by combination of ATO and radiation. Radiation-induced matrix metalloproteinase-9 (MMP-9) expression was significantly inhibited by ATO using sequential analysis of the expression of MMPs in xenografts. Supporting this observation, ATO directly downregulates radiation-induced MMP-9 mRNA expression by inhibiting nuclear factor κB activity in human cervical cancer cells. In sum, concurrent arsenic–radiation therapy not only achieves local tumor control but also inhibits distant metastasis. Experimental results of this study highlight a novel strategy in cancer treatment.

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Acknowledgements

We thank Dr Yung-Ming Jeng (Department of Pathology, National Taiwan University Hospital) for review of histological work presented in this study and Julie Yu for carefully reading the manuscript. This work was supported by grant from National Taiwan University Hospital 92-S016.

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Authors and Affiliations

  1. Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Lin-Hung Wei, Kuo-Pao Lai, Chia-Hsien Cheng & Yun-Ju Huang

  2. Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

    Chi-An Chen & Chang-Yao Hsieh

  3. Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Hung Chou & Min-Liang Kuo

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  1. Lin-Hung Wei
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Correspondence to Chang-Yao Hsieh.

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Wei, LH., Lai, KP., Chen, CA. et al. Arsenic trioxide prevents radiation-enhanced tumor invasiveness and inhibits matrix metalloproteinase-9 through downregulation of nuclear factor κB. Oncogene 24, 390–398 (2005). https://doi.org/10.1038/sj.onc.1208192

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