Research Papers:
(E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibits growth of colon tumors in mice
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Abstract
Jie Zheng1,*, Mi Hee Park1,*, Dong Ju Son1, Min Gi Choi1, Jeong Soon Choi1, Kyung Tak Nam1, Hae Deun Kim1, Kevin Rodriguez2, Benjamin Gann2, Young Wan Ham2, Sang Bae Han1 and Jin Tae Hong1
1 College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea
2 Department of Chemistry, Utah Valley University, Orem, UT, USA
* These authors have contributed equally to this work
Correspondence to:
Jin Tae Hong, email:
Sang Bae Han, email:
Keywords: colon cancer, apoptosis, STAT3, NF-κB, death receptor
Received: June 08, 2015 Accepted: August 31, 2015 Published: October 14, 2015
Abstract
In our previous study, we found that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal showed anti-cancer effect, but it showed lack of stability and drug likeness. We have prepared several (E)-2,4-bis(p-hydroxyphenyl)-2-butenal analogues by Heck reaction. We selected two compounds which showed significant inhibitory effect of colon cancer cell growth. Thus, we evaluated the anti-cancer effects and possible mechanisms of one compound (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol in vitro and in vivo. In this study, we found that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol induced apoptotic cell death in a dose dependent manner (0-15 μg/ml) through activation of Fas and death receptor (DR) 3 in HCT116 and SW480 colon cancer cell lines. Moreover, the combination treatment with (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol and nuclear factor κB (NF-κB) inhibitor, phenylarsine oxide (0.1 μM) or signal transducer and activator of transcription 3 (STAT3) inhibitor, Stattic (50 μM) increased the expression of Fas and DR3 more significantly. In addition, (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol suppressed the DNA binding activity of both STAT3 and NF-κB. Knock down of STAT3 or NF-κB p50 subunit by STAT3 small interfering RNA (siRNA) or p50 siRNA magnified (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol-induced inhibitory effect on colon cancer cell growth. Besides, the expression of Fas and DR3 was increased in STAT3 siRNA or p50 siRNA transfected cells. Moreover, docking model and pull-down assay showed that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol directly bound to STAT3 and NF-κB p50 subunit. Furthermore, (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibited colon tumor growth in a dose dependent manner (2.5 mg/kg-5 mg/kg) in mice. Therefore, these findings indicated that (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol may be a promising anti-cancer agent for colon cancer with more advanced research.
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