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Article

Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

1
Department of Digestive Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
2
Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo 101-8309, Japan
3
Department of Anatomy, Nihon University School of Dentistry, Tokyo 101-8310, Japan
4
Sasaki Foundation, Department of Medicine, Kyoundo Hospital, Tokyo 101-0062, Japan
5
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan
6
Department of Physiology, Nihon University School of Medicine, Tokyo 173-8610, Japan
7
Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo 173-8610, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Chiara Brullo
Molecules 2020, 25(12), 2883; https://doi.org/10.3390/molecules25122883
Received: 17 May 2020 / Revised: 12 June 2020 / Accepted: 20 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Anticancer Compounds with Different Biological Targets)
Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer. View Full-Text
Keywords: pyrrole-imidazole polyamide; TGF-β1; liver cancer; cancer stem cell; novel candidate drug pyrrole-imidazole polyamide; TGF-β1; liver cancer; cancer stem cell; novel candidate drug
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MDPI and ACS Style

Takagi, K.; Midorikawa, Y.; Takayama, T.; Abe, H.; Fujiwara, K.; Soma, M.; Nagase, H.; Miki, T.; Fukuda, N. Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells. Molecules 2020, 25, 2883. https://doi.org/10.3390/molecules25122883

AMA Style

Takagi K, Midorikawa Y, Takayama T, Abe H, Fujiwara K, Soma M, Nagase H, Miki T, Fukuda N. Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells. Molecules. 2020; 25(12):2883. https://doi.org/10.3390/molecules25122883

Chicago/Turabian Style

Takagi, Keiko, Yutaka Midorikawa, Tadatoshi Takayama, Hayato Abe, Kyoko Fujiwara, Masayoshi Soma, Hiroki Nagase, Toshio Miki, and Noboru Fukuda. 2020. "Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells" Molecules 25, no. 12: 2883. https://doi.org/10.3390/molecules25122883

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