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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells
Sakthivel Muniyan1, Yu-Wei Chou2, Matthew A Ingersoll1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Abstract:
Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.
Insights
Novel imidazopyridine derivatives, AMD and DME, show potent antiproliferative effects against castration-resistant prostate cancer (CR PCa) cells. These compounds inhibit key signaling pathways and induce apoptosis, offering potential new therapeutic strategies for CR PCa.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Pharmacology
Background:
- Metastatic prostate cancer (mPCa) frequently progresses to castration-resistant prostate cancer (CR PCa) despite androgen deprivation therapy (ADT).
- Limited treatment options exist for CR PCa, necessitating the development of novel therapeutic agents.
Purpose of the Study:
- To evaluate the antiproliferative activities of novel imidazopyridine derivatives against prostate cancer cells.
- To identify promising compounds for the potential treatment of castration-resistant prostate cancer.
Main Methods:
- Screening of imidazopyridine derivatives (PHE, AMD, AMN) for antiproliferative activity on LNCaP C-81 cells.
- Assessment of derivative DME's efficacy compared to AMD on prostate cancer cell proliferation, clonogenic potential, and in vitro tumorigenicity.
- Investigation of apoptosis induction and inhibition of androgen receptor (AR) and PI3K/Akt signaling pathways.
Main Results:
- AMD demonstrated significant dose- and time-dependent inhibition of LNCaP C-81 cell proliferation and showed selectivity against cancer cells over normal prostate cells.
- DME exhibited superior inhibitory activity compared to AMD regarding cell proliferation, clonogenic potential, and in vitro tumorigenicity.
- Both AMD and DME treatments induced apoptosis and inhibited AR and PI3K/Akt signaling pathways.
Conclusions:
- Novel imidazopyridine derivatives, particularly DME, possess significant antiproliferative and anti-tumorigenic properties against prostate cancer cells.
- The observed effects are partly mediated by apoptosis induction and inhibition of AR and PI3K/Akt signaling.
- Further understanding of these mechanisms could lead to the development of novel therapeutics for CR PCa.
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