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

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.

Combined anticancer therapy with imidazoacridinone analogue C‐1305 and paclitaxel in human lung and colon cancer xenografts—Modulation of tumour angiogenesis

“…Furthermore, recent studies revealed that C‐1311 facilitated the restoration of the DNA damage response cascade in androgen‐dependent prostate cancer cells. In contrast, C‐1311 targeted cellular metabolism and inhibited the genes responsible for the regulation of glycolysis and gluconeogenesis pathways in androgen‐independent prostate cancer cells 21 . Moreover, both compounds, C‐1305 and C‐1311 are selective inhibitors of cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes 22,23 .…”

“…In contrast, C-1311 targeted cellular metabolism and inhibited the genes responsible for the regulation of glycolysis and gluconeogenesis pathways in androgen-independent prostate cancer cells. 21 Moreover, both compounds, C-1305 and C-1311 are selective inhibitors of cytochrome P450 (CYP) 1A2 and 3A4 isoenzymes. 22,23 F I G U R E 6 The analysis of ERK1/2, Akt and p38α phosphorylation and expression in HCT116 tumour lysates.…”

Synthesis and Application in Cell Imaging of Acridone Derivatives

“…Acronycine, a natural acridone alkaloid isolated from Acronychia baueri, has significant anticancer activities as a result of its interference in DNA replication of tumor cells [5,6]. A potent anticancer drug, C1311, which is in progress in clinical trials, can bind tumor DNA to inhibit the proliferation of cancer cells [7]. Moreover, several artificial acridone derivatives have acquired the antibacterial and anticancer abilities by incorporating an alkyl chain onto the N-position, such as with pyrimidocarvazones or pyrimidoacridone, respectively [8,9].…”