Prostate cancer (PCa) is the most prevailing cancer and the fifth leading reason for increased mortality rate in males.
The high progression of PCa all over the worldwide has raised the challenge of developing new drugs or combinational therapy that targets various signaling pathways involved in DNA damage and epigenetics. Therefore, further investigation on the mysterious molecular mechanisms underlying the progression and treatment of PCa, could greatly improve the life quality and the survival rate of PCa patients.
G protein-coupled receptors (GPCRs), the largest family of cell membrane receptor, was noticed as the “work-horses” of physiology, with nearly 35% of the drugs targeting this receptor.
Among 1000 members of GPCRs, expression of P2Y purinergic receptor 1 (P2Y1R) is found to be abundant in human prostate tissues. Notably, P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells. Thus, P2Y1R is considered as a suitable candidate for further evaluation in this study.
In her doctoral study, Hien Le identified a novel synthetic alkylamino phenolic derivative targeting P2Y1 purinergic receptor to combat PCa proliferation and metastasis. Phenolic compounds are ubiquitous in organic chemistry that evidenced the therapeutic benefits through the inhibition of cancer cell proliferation. Phenolic compounds have the ability to induce DNA damage, apoptosis, and cell phase arrest and to impede cell migration and invasion. She performed extensive high throughput screening of about 1000s of compounds targeting P2Y1R.
The study indicated that two phenolic compounds, 1-(2-Hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile) (HIC) and Methyl 4-((4-cyanoindolin-1-yl)(2,5-dihydroxyphenyl)methyl)benzoate) could act as novel selective agonists of P2Y1R.
Hien Le performed pharmacokinetic and dynamic studies including colony, spheroid, apoptosis, caspase activity, reactive oxygen species (ROS), mitochondrial activity, glutathione, and cell cycle assays. Moreover, RNA sequencing and protein microarray were carried out to identify the significant genes, proteins, signaling pathways upon downstream signaling cascade activation of P2Y1R regulated by the HIC.
Hien Le’s investigation revealed HIC to have the potential inhibitory ability by modulating apoptotic response, cell phase arrest, and DNA damage. In addition, the study reports that HIC could inhibit PCa cell proliferation and induce cell death through ROS-mediated apoptosis.
Through her studies, Hien Le found that the interaction of P2Y1-HIC regulates numerous signaling pathways such as p53-p21, TGF-β, and PAPR. Furthermore, a combinatorial of HIC with abiraterone acetate (AA), a known clinic drug targeted towards androgen receptor (AR) in PCa treatment, showed promising anticancer properties in androgen independent PCa models.
Hien Li explored the potential of the combinatorial drugs inhibiting cell proliferation, inducing apoptosis and cell cycle arrest. Therefore, the combination of HIC and AA can be used as a novel therapy for treating prostate cancer.
The completed study was conducted in the Molecular Signaling Group, under the supervision of Adjunct Professor, PhD Meenakshisundaram Kandhavelu, University Lecturer and Professor, PhD Olli Yli-Harja, Computational Systems Biology Group from the Faculty of Medicine and Health Technology, Tampere University.
The doctoral dissertation of M. Pharm Hien Le in the field of Biomedical Sciences and Engineering entitled A novel synthetic agonist of P2Y1 purinergic receptor acts as an anticancer drug for prostate cancer treatment will be publicly examined in the Faculty of Medicine and Health Technology of Tampere University at 15.00 EET, on Tuesday 20 December 2022. The opponent will be Professor, PhD Arun K. Sharma from Penn State College of Medicine, Hershey, Pennsylvania, USA. The Custos will be Professor, PhD Olli Yli-Harja from the Faculty of Medicine and Health Technology, Tampere University.
The event can be followed via remote connection.
The dissertation is also available online at
https://urn.fi/URN:ISBN:978-952-03-2692-0
The Faculty Office will provide a pdf version of the entire doctoral dissertation upon request. Please send an email to met.doc.tau [at] tuni.fi
Photographer: Anh Hoang