A flavonoid chrysin suppresses hypoxic survival and metastatic growth of mouse breast cancer cells

Lirdprapamongkol,Kriengsak; Sakurai,Hiroaki; Abdelhamed,Sherif; Yokoyama,Satoru; Maruyama,Takeyuki; Athikomkulchai,Sirivan; Viriyaroj,Amornrat; Awale,Suresh; Yagita,Hideo; Ruchirawat,Somsak; Svasti,Jisnuson; Saiki,Ikuo

doi:10.3892/or.2013.2667

A flavonoid chrysin suppresses hypoxic survival and metastatic growth of mouse breast cancer cells

Authors:
- Kriengsak Lirdprapamongkol
- Hiroaki Sakurai
- Sherif Abdelhamed
- Satoru Yokoyama
- Takeyuki Maruyama
- Sirivan Athikomkulchai
- Amornrat Viriyaroj
- Suresh Awale
- Hideo Yagita
- Somsak Ruchirawat
- Jisnuson Svasti
- Ikuo Saiki
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Affiliations: Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand, Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan, Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok 26120, Thailand, Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan, Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
Published online on: August 20, 2013 https://doi.org/10.3892/or.2013.2667
Pages: 2357-2364

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Abstract

Tumor hypoxia commonly occurs in solid tumors, and correlates with metastasis. Current cancer therapies are inefficient in curing metastatic disease. Herein, we examined effect of Thai propolis extract and its major constituent, chrysin, on hypoxic survival of 4T1 mouse breast cancer cells in vitro, and investigated its underlying mechanism. In vivo effect of chrysin on metastatic progression of cancer cells was studied, both as a single agent and in combination with another antimetastatic agent, agonistic monoclonal antibody targeting the DR5 TRAIL receptor (DR5 mAb). Thai propolis extract and chrysin decreased survival of 4T1 cells after exposure to hypoxia (1% O2), for 2 days. Immunoblot analysis revealed that chrysin inhibited hypoxia-induced STAT3 phosphorylation without affecting HIF-1α protein level. Chrysin also abrogated hypoxia-induced VEGF gene expression as determined by qRT-PCR. The in vivo effect of chrysin was determined in a spontaneous metastasis mouse model of breast cancer, either alone or in combination with DR5 mAb. Daily oral administration of chrysin in Balb/c mice implanted with 4T1 cells significantly suppressed growth of lung metastatic colonies. Moreover, antimetastatic activity of DR5 mAb was enhanced when given in combination with chrysin. We demonstrate that chrysin has potential in controlling metastatic progression.

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