P2Y1 agonist HIC in combination with androgen receptor inhibitor abiraterone acetate impairs cell growth of prostate cancer

Hien Thi Thu Le,Olli Yli-Harja,Thiyagarajan Ramesh,Nuno R Candeias,Meenakshisundaram Kandhavelu,Akshaya Murugesan

doi:10.1007/s10495-022-01716-1

Abstract

P2Y receptors belong to the large superfamily of G-protein-coupled receptors and play a crucial role in cell death and survival. P2Y1 receptor has been identified as a marker for prostate cancer (PCa). A previously unveiled selective P2Y1 receptor agonist, the indoline-derived HIC (1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile), induces a series of molecular and biological responses in PCa cells PC3 and DU145, but minimal toxicity to normal cells. Here, we evaluated the combinatorial effect of HIC with abiraterone acetate (AA) targeted on androgen receptor (AR) on the inhibition of PCa cells. Here, the presence of HIC and AA significantly inhibited cell proliferation of PC3 and DU145 cells with time-dependent manner as a synerfistic combination. Moreover, it was also shown that the anticancer and antimetastasis effects of the combinratorial drugs were noticed through a decrease in colony-forming ability, cell migration, and cell invasion. In addition, the HIC + AA induced apoptotic population of PCa cells as well as cell cycle arrest in G1 progression phase. In summary, these studies show that the combination of P2Y1 receptor agonist, HIC and AR inhibitor, AA, effectively improved the antitumor activity of each drug. Thus, the combinatorial model of HIC and AA should be a novel and promising therapeutic strategy for treating prostate cancer.

Highlights

Prostate cancer (PCa) is the most common malignant tumour diagnosed in men around the world [1]
To assess the effective concentrations of HIC and AA (Fig. 1A) on cell death, PCa and non-cancer cells were incubated with increasing concentrations of HIC and AA for 48 h and cell viability was determined by MTT assay
The cell death was observed at about 34.6 ± 1.8% and 43.6 ± 1.9% in PC3 and DU145 cells at 40 μM AA treatment

Summary

Introduction

Prostate cancer (PCa) is the most common malignant tumour diagnosed in men around the world [1]. The disease can still progress and be resistant to the primary treatment Such a type of cancer is called castrate-resistant PCa (CRPC) [12]. In androgen receptor (AR)-positive cell line (LNCap cells), the anticancer effect of androgen biosynthesis inhibitor AA was observed to occur via the degradation of the CYP17A1 enzyme. This cytochrome P450, family 17, subfamily A, polypeptide 1 enzyme is crucial for androgen-dependent cancers and hyperplasia [13, 14]. The activity of HIC was identified as a potential drug-like compound again the growth of PC3 and DU145, the combinatorial effect of HIC along with any known clinical drug is yet to be investigated

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