title: (E)-4-(3-(3,5-dimethoxyphenyl)allyl)-2-methoxyphenol inhibits growth of colon tumors in mice.
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.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Min Gi
authors.initials: MG
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jeong Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Kyung Tak
authors.initials: KT
authors.lastname: Nam
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Hae Deun
authors.initials: HD
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Utah Valley University, Orem, UT, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rodriguez
authors.affiliation: Department of Chemistry, Utah Valley University, Orem, UT, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gann
authors.affiliation: Department of Chemistry, Utah Valley University, Orem, UT, USA.
authors.forename: Young Wan
authors.initials: YW
authors.lastname: Ham
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Heungduk-gu, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000498:Allyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D034622:RNA Interference; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000498:Allyl Compounds; D000970:Antineoplastic Agents; D001152:Arsenicals; D003499:Cyclic S-Oxides; C491901:FAS protein, human; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D010636:Phenols; D053219:Receptors, Tumor Necrosis Factor, Member 25; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C506033:TNFRSF25 protein, human; D019014:fas Receptor; C517409:stattic; C029341:oxophenylarsine
keywords: NF-κB; STAT3; apoptosis; colon cancer; death receptor