Oncotarget

Research Papers:

(E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibits growth of colon tumors in mice

Jie Zheng, Mi Hee Park, Dong Ju Son, Min Gi Choi, Jeong Soon Choi, Kyung Tak Nam, Hae Deun Kim, Kevin Rodriguez, Benjamin Gann, Young Wan Ham, Sang Bae Han and Jin Tae Hong _

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Oncotarget. 2015; 6:41929-41943. https://doi.org/10.18632/oncotarget.5861

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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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