Preprint Article Version 1 This version is not peer-reviewed

The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin

Version 1 : Received: 1 March 2019 / Approved: 4 March 2019 / Online: 4 March 2019 (13:37:02 CET)

How to cite: Amawi, H.; Hussein, N.; Boddu, S.H.; Karthikeyan, C.; Williams, F.E.; Ashby Jr., C.R.; Dayanidhi, R.; Trivedi, P.; Tiwari, A. The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin. Preprints 2019, 2019030045 (doi: 10.20944/preprints201903.0045.v1). Amawi, H.; Hussein, N.; Boddu, S.H.; Karthikeyan, C.; Williams, F.E.; Ashby Jr., C.R.; Dayanidhi, R.; Trivedi, P.; Tiwari, A. The Novel Thienopyrimidine Derivative, RP-010, Produces Its Efficacy in Prostate Cancer Cells by Inducing the Fragmentation of β-catenin. Preprints 2019, 2019030045 (doi: 10.20944/preprints201903.0045.v1).

Abstract

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

Subject Areas

Thienopyrimidines, RP-010, Prostate cancer, Metastasis, Wnt/β-catenin, Apoptosis.

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