A small molecule, (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol suppresses tumor growth via inhibition of IkappaB kinase β in colorectal cancer in vivo and in vitro
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Jie Zheng1,3,*, Mi Hee Park1,*, Hee Pom Lee1, Byung Kook Hyun1, Hyung Ok Chun1, Sung Hee Jung1, Hyun Ok Seo1, Young Wan Ham2, Sang-Bae Han1 and Jin Tae Hong1
1College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea
2Department of Chemistry, Utah Valley University 800 W, University Pkwy, Orem, UT 84058, USA
3Current address: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
*These authors have contributed equally to this work
Jin Tae Hong, email: [email protected]
Sang-Bae Han, email: [email protected]
Keywords: MMPP, colon cancer, IKKβ, death receptor, tumor growth inhibition
Received: March 24, 2017 Accepted: July 26, 2017 Published: August 24, 2017
Here we report that a novel synthesized compound (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) which exhibits better stability, drug-likeness and anti-cancer effect than (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB) that we previously reported. Of all newly synthesized BHPB analogues, MMPP showed the most significant inhibitory effect on colon cancer cell growth. Thus, we evaluated the anti-cancer effects and possible mechanisms of MMPP in vitro and in vivo. MMPP treatment (0-15 μg/mL) induced apoptotic cell death and enhanced the expression of cleaved caspase-3 and cleaved caspase-8 in a concentration dependent manner. Notably, the expression of death receptor (DR)5 and DR6 was significantly increased by MMPP treatment. Moreover, DR5 siRNA or DR6 siRNA transfection partially abolished MMPP-induced cell growth inhibition. Pull down assay and docking experiment showed that MMPP bound directly to IkappaB kinase β (IKKβ). It was noteworthy that IKKβ mutant (C99S) partially abolished MMPP-induced cell growth inhibition and enhanced expression of DR5 and DR6. In addition, MMPP enhanced TRAIL-induced apoptosis, cell growth inhibition and expression of DRs. In xenograft mice model, MMPP (2.5-5 mg/kg) suppressed tumor growth in a dose dependent manner. Immunohistochemistry analysis showed that the expression levels of DR5 and DR6 and active caspase-3 were increased while the expression levels of PCNA and p-IKKβ were decreased in a dose dependent manner. Thus, MMPP may be a promising anti-cancer agent in colon cancer treatment.
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