Research Papers:

Molecular mechanisms underlying the antitumor activity of (E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide in human colorectal cancer cells in vitro and in vivo

Chun-Han Chen _, Chia-Hwa Lee, Jing-Ping Liou, Che-Ming Teng and Shiow-Lin Pan

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Oncotarget. 2015; 6:35991-36002. https://doi.org/10.18632/oncotarget.5475

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Chun-Han Chen1, Chia-Hwa Lee3, Jing-Ping Liou2, Che-Ming Teng3, Shiow-Lin Pan1

1The Ph.D. program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan

3Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan

Correspondence to:

Shiow-Lin Pan, e-mail: [email protected]

Keywords: CRC, HDAC, apoptosis, EMT, Akt

Received: May 05, 2015     Accepted: September 24, 2015     Published: October 05, 2015


Upregulation of class I histone deacetylases (HDAC) correlates with poor prognosis in colorectal cancer (CRC) patients. Previous study revealed that (E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide (Compound 11) is a potent and selective class I HDAC inhibitor, exhibited significant anti-proliferative activity in various human cancer cell lines. In current study, we demonstrated that compound 11 exhibited significant anti-proliferative and cytotoxic activity in CRC cells. Notably, compound 11 was less potent than SAHA in inhibiting HDAC6 as evident from the lower expression of acetyl-α-tubulin, suggesting higher selectivity for class I HDACs. Mechanistically, compound 11 induced cell-cycle arrest at the G2/M phase, activated both intrinsic- and extrinsic-apoptotic pathways, altered the expression of Bcl-2 family proteins and exerted a potent inhibitory effect on survival signals (p-Akt, p-ERK) in CRC cells. Moreover, we provide evidence that compound 11 suppressed motility, decreased mesenchymal markers (N-cadherin and vimentin) and increased epithelial marker (E-cadherin) through down-regulation of Akt. The anti-tumor activity and underlying molecular mechanisms of compound 11 were further confirmed using the HCT116 xenograft model in vivo. Our findings provide evidence of the significant anti-tumor activity of compound 11 in a preclinical model, supporting its potential as a novel therapeutic agent for CRC.

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