Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells.

Magdalena Niemira,Mirosław Kwaśniewski,Adrianna Moszyńska,Anna Skwarska,Samuel B Bader,Barbara Borowa-Mazgaj,Marcin Ratajewski,Adam Krętowski,Zofia Mazerska,Kaja Karaś,Ester M Hammond

doi:10.3390/biomedicines8090292

Abstract

The androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and metastasis. Thus, blocking AR activity and its downstream signaling constitutes a major strategy for PCa treatment. Here, we report on the potent anti-PCa activity of a small-molecule imidazoacridinone, C-1311. In AR-positive PCa cells, C-1311 was found to inhibit the transcriptional activity of AR, uncovering a novel mechanism that may be relevant for its anticancer effect. Mechanistically, C-1311 decreased the AR binding to the prostate-specific antigen (PSA) promoter, reduced the PSA protein level, and, as shown by transcriptome sequencing, downregulated numerous AR target genes. Importantly, AR-negative PCa cells were also sensitive to C-1311, suggesting a promising efficacy in the androgen-independent PCa sub-type. Irrespective of AR status, C-1311 induced DNA damage, arrested cell cycle progression, and induced apoptosis. RNA sequencing indicated significant differences in the transcriptional response to C-1311 between the PCa cells. Gene ontology analysis showed that in AR-dependent PCa cells, C-1311 mainly affected the DNA damage response pathways. In contrast, in AR-independent PCa cells, C-1311 targeted the cellular metabolism and inhibited the genes regulating glycolysis and gluconeogenesis. Together, these results indicate that C-1311 warrants further development for the treatment of PCa.

Highlights

Prostate cancer (PCa) remains one of the most common cancers in the male population and has a poor prognosis
Imidazoacridinones Are Potent Against androgen receptor (AR)-Dependent prostate cancer (PCa) Cells
We examined the in vitro cytotoxic activity of the imidazoacridinones (Figure S1A) and their close analogs, the triazoloacridinones (Figure S1B), which contain a triazole ring condensed with the acridinone chromophore

Summary

Introduction

Prostate cancer (PCa) remains one of the most common cancers in the male population and has a poor prognosis. PCa is a highly heterogeneous disease, at both the molecular and cellular level, with a complex pattern of metastatic spread [3]. Such heterogeneity underlies the mixed response of PCa cells to treatment, highlighting the need for multi-targeted therapies. Often termed metastatic castration-resistant PCa (mCRPC), may still have abnormally activated AR signaling pathways that fuel tumor survival and proliferation even in the presence of ADT [7]. In this context, novel therapeutic agents that target the AR are urgently required

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