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Adenosine A3 receptor antagonists as anti-tumor treatment in human prostate cancer: an in vitro study
Maria Beatrice Morelli1, Andrea Spinaci2, Cui Chang2
1Experimental Medicine Unit, School of Pharmacy, University of Camerino, Italy.
Abstract:
Prostate cancer (PCa) is one of the most common cancers in men, and for patients with PCa that cannot be surgically resected or treated, androgen suppression therapy often results in significant adverse effects. Recent studies have shown that A3 adenosine receptors (A3ARs) are overexpressed in prostate cancer (PCa), and several A3AR agonists and antagonists have been investigated as potential anticancer drugs. In this study, we investigated the potential therapeutic effects of the A3AR antagonists AR 292 and AR 357 in human PCa cell lines. LNCaP, DU-145, and PC3 cell lines were treated with AR 292 and AR 357 compounds, and their cytotoxic effects were determined using viability assays, flow cytometry, and western blotting. Moreover, the drug transporter gene profile was evaluated using RT-PCR in untreated and A3AR antagonist-treated PCa cells. Both AR 292 and AR 357 showed antiproliferative effects with significant cell cycle arrest and induced DNA damage leading to cell death. AR 292 and especially AR 357 modulated the expression of drug transporter genes involved in chemoresistance, ferroptosis, and the hypoxia response. Ferroptosis was induced in DU-145 cells treated with both compounds as well as in PC3 cells treated with AR 357. However, the treatment of PC3 cells with AR 292 and the treatment of LNCaP cells with both AR 292 and AR 357 resulted in necrotic cell death. In conclusion, our study showed that A3AR ligands exert anticancer effects via different mechanisms on PCa cell lines through the activation of multiple molecular pathways.
Insights
New A3 adenosine receptor antagonists, AR 292 and AR 357, show promise in treating prostate cancer (PCa). These compounds induce cell death and alter key molecular pathways, offering potential new therapeutic strategies for PCa patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) is a prevalent malignancy in men, often requiring treatments with significant side effects.
- A3 adenosine receptors (A3ARs) are overexpressed in PCa, making them a target for novel therapeutics.
- Current treatments like androgen suppression therapy can lead to adverse effects, necessitating alternative approaches.
Purpose of the Study:
- To investigate the therapeutic potential of A3AR antagonists AR 292 and AR 357 in human prostate cancer cell lines.
- To evaluate the cytotoxic effects, cell cycle modulation, and DNA damage induced by these antagonists.
- To analyze the impact of A3AR antagonists on drug transporter gene expression related to chemoresistance and cellular stress responses.
Main Methods:
- Treatment of LNCaP, DU-145, and PC3 prostate cancer cell lines with AR 292 and AR 357.
- Assessment of cell viability, cell cycle progression, and DNA damage using assays like flow cytometry and western blotting.
- Evaluation of drug transporter gene expression profiles via RT-PCR in treated and untreated cells.
Main Results:
- Both AR 292 and AR 357 demonstrated antiproliferative effects, inducing cell cycle arrest and DNA damage, leading to cell death.
- AR 292 and AR 357 modulated drug transporter genes involved in chemoresistance, ferroptosis, and hypoxia response.
- Specific cell death pathways were observed, including ferroptosis in DU-145 and PC3 cells (with AR 357), and necrosis in PC3 (with AR 292) and LNCaP cells (with both compounds).
Conclusions:
- A3AR antagonists AR 292 and AR 357 exhibit significant anticancer effects against prostate cancer cell lines.
- These compounds activate diverse molecular pathways, including those regulating cell cycle, DNA damage, ferroptosis, and necrosis.
- A3AR-targeted therapies represent a promising strategy for prostate cancer treatment, potentially overcoming resistance mechanisms.
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