PUBLICATION
Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells
- Authors
- Amawi, H., Hussein, N., Boddu, S.H.S., Karthikeyan, C., Williams, F.E., Ashby, C.R., Raman, D., Trivedi, P., Tiwari, A.K.
- ID
- ZDB-PUB-190528-8
- Date
- 2019
- Source
- Cancers 11(5): (Journal)
- Registered Authors
- Williams, Fred
- Keywords
- RP-010, Wnt/β-catenin, apoptosis, metastasis, prostate cancer, thienopyrimidines
- MeSH Terms
- none
- PubMed
- 31126091 Full text @ Cancers
Citation
Amawi, H., Hussein, N., Boddu, S.H.S., Karthikeyan, C., Williams, F.E., Ashby, C.R., Raman, D., Trivedi, P., Tiwari, A.K. (2019) Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells. Cancers. 11(5).
Abstract
Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.
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