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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Dual PI3K-BRD4 Inhibitor SF1126 Inhibits Colorectal Cancer Cell Growth in Vitro and in Vivo
An-Cheng Qin1, Ya Li2, Li-Na Zhou3
1Department of Hepatobiliary Surgery, Suzhou Municipal Hospital affiliated to Nanjing Medical University, Suzhou, China.
Background/Aims:
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are key oncogenic cascades in colorectal cancer (CRC). SF1126 is a novel and potent PI3K-BRD4 dual inhibitor.
Methods:
CRC cells and human colon epithelial cells were treated with SF1126. Cell survival was tested by MTT and soft agar colony formation assays. Cell proliferation was tested by BrdU ELISA method. Cell apoptosis was tested by a TUNEL staining method and Histone DNA ELISA. Western blotting was utilized to test the signaling proteins. A HT-29 xenograft mice model was established to study the anti-tumor activity of SF1126 in vivo.
Results:
SF1126 potently inhibited the survival, proliferation, and progression of the cell cycle in an established CRC cell line (HT-29) and primary human colon cancer cells. Significant activation of apoptosis was detected in SF1126-treated CRC cells. In CRC cells, SF1126 blocked Akt-mammalian target of rapamycin (mTOR) complex1/2 signaling and downregulated BRD4 target proteins (Myc and cyclin D1). Further studies showed that SF1126 activated p38 signaling in CRC cells. In contrast, the p38 inhibitors or p38 short hairpin RNA inhibited SF1126-induced cytotoxicity and apoptosis in CRC cells. In vivo, subcutaneous administration of SF1126 significantly inhibited HT-29 xenograft tumor growth in nude mice.
Conclusion:
SF1126 inhibits CRC cell growth possibly by targeting PI3K-Akt-mTOR, BRD4, and p38 signaling.
Insights
SF1126, a novel PI3K-BRD4 inhibitor, effectively suppressed colorectal cancer (CRC) cell growth and tumor development by targeting key oncogenic pathways, including PI3K-Akt-mTOR, BRD4, and p38 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are critical oncogenic drivers in colorectal cancer (CRC).
- SF1126 is a newly developed dual inhibitor targeting both PI3K and BRD4 pathways.
Purpose of the Study:
- To investigate the anti-cancer effects of SF1126 in colorectal cancer.
- To elucidate the molecular mechanisms underlying SF1126's action in CRC cells.
Main Methods:
- SF1126 treatment on CRC and colon epithelial cells.
- Assays for cell survival (MTT, soft agar), proliferation (BrdU ELISA), and apoptosis (TUNEL, Histone DNA ELISA).
- Western blotting for signaling proteins and in vivo studies using a HT-29 xenograft mouse model.
Main Results:
- SF1126 inhibited CRC cell survival, proliferation, and cell cycle progression, inducing apoptosis.
- SF1126 downregulated PI3K-Akt-mTOR signaling and BRD4 targets (Myc, cyclin D1) while activating p38 signaling.
- In vivo, SF1126 significantly suppressed HT-29 xenograft tumor growth.
Conclusions:
- SF1126 demonstrates potent anti-tumor activity against colorectal cancer.
- The drug's efficacy is mediated through the inhibition of PI3K-Akt-mTOR, BRD4, and activation of p38 signaling pathways.
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