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Published on: March 6, 2018
Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells
Matthew A Ingersoll1, Anastesia S Lyons2, Sakthivel Muniyan1
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.
Insights
Novel imidazopyridine derivatives, HIMP and M-MeI, show promise in treating castration-resistant prostate cancer (PCa). M-MeI selectively inhibits PCa cell growth by targeting key signaling pathways, offering a potential new therapy for advanced prostate cancer.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in US males.
- Current treatments for metastatic PCa, including androgen-deprivation therapy and anti-androgens, often lead to therapy resistance and castration-resistant PCa (CRPC).
- There is a critical need for novel therapeutic agents to treat CRPC.
Purpose of the Study:
- To investigate the inhibitory effects of novel imidazopyridine derivatives (HIMP, M-MeI, OMP, EtOP) on human castration-resistant prostate cancer cells.
- To identify potent compounds for CRPC therapy.
- To elucidate the mechanisms of action for promising compounds.
Main Methods:
- Screening of novel imidazopyridine derivatives against human CRPC cell lines.
- Assessing dose- and time-dependent effects on cell proliferation, colony formation, adhesion, and migration.
- Investigating the impact on PI3K/Akt and androgen receptor signaling pathways.
- Cell cycle analysis.
Main Results:
- HIMP and M-MeI demonstrated selective, dose- and time-dependent inhibition of CRPC cell proliferation, sparing benign prostate cells.
- M-MeI exhibited the most potent effects in reducing colony formation, cell adhesion, and migration.
- HIMP primarily inhibited the PI3K/Akt pathway, while M-MeI targeted both PI3K/Akt and androgen receptor pathways, leading to G2 cell cycle arrest.
Conclusions:
- Novel imidazopyridine derivatives, particularly M-MeI, show significant potential as therapeutic agents for castration-resistant prostate cancer.
- M-MeI's dual inhibition of PI3K/Akt and androgen receptor pathways offers a promising strategy for CRPC treatment.
- Further research into imidazopyridine mechanisms could lead to more effective anti-PCa drug development.
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