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

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.

• 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
• Journal: Oncology reports (Oncol Rep) Vol. 30 Issue 5 Pg. 2357-64 (Nov 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23969634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• STAT3 Transcription Factor
• chrysin

Topics

• Animals
• Breast Neoplasms (drug therapy, pathology)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Flavonoids (administration & dosage, chemistry)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Neoplasm Metastasis (drug therapy, pathology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics)
• STAT3 Transcription Factor (genetics)