Abstract
BackgroundThe aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood.MethodsIn this study, microarray gene expression analysis comparing FX-9 exposed and unexposed prostate cancer cells (PC-3 representing castration-resistant prostate cancer), followed by pathway analysis and gene annotation to functional processes were performed. Immunocytochemistry staining was performed with selected targets.ResultsExpression analysis revealed 0.83% of 21,448 differential expressed genes (DEGs) after 6-h exposure of FX-9 and 0.68% DEGs after 12-h exposure thereof. Functional annotation showed that FX-9 primarily caused an activation of inflammatory response by non-canonical nuclear factor-kappa B (NF-κB) signaling. The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples. This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1, including downstream target genes, resulting in G1-phase arrest. Matching our previous observations on cellular level senescence signaling pathways were also found enriched. To verify these results immunocytochemical staining of p21 Waf1/Cip1 (CDKN1A), E2F1 (E2F1), PAI-1 (SERPNE1), and NFkB2/NFkB p 100 (NFKB2) was performed. Increased expression of p21 Waf1/Cip1 and NFkB2/NFkB p 100 after 24-h exposure to FX-9 was shown. E2F1 and PAI-1 showed no increased expression.ConclusionsFX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A, which was initiated by an inflammatory response of noncanonical NF-κB signaling.
Highlights
The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells
PC-3 expressed 18,722 of these genes, and after 6-h exposure to 5 μM FX-9, 179 genes were differentially expressed compared to untreated controls
The expression of 78 genes was decreased with fold change between − 2 and − 3.41.Gene expression analysis after exposure to 5 μM FX-9 over a 12-h period revealed a total of 145 differential expressed genes (DEGs) compared to non-treated control samples
Summary
The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. Decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. Previous studies by us proved anti-proliferative effects of FX-9 on hematological and solid tumor cell lines. This effect was accompanied with morphological changes and apoptosis in lymphoblastic leukemia cells, while cytotoxicity and hemolytic activity against non-neoplastic blood cells were not observed [7]. The effects on prostate cancer cells lines of human and canine origin were pro-apoptotic and antimitotic. This was evaluated by analyzing cell viability, total cell number, cell morphological changes and induction of apoptosis [8]. FX-9mediated cytotoxic activity in non-malignant chondrocytes and fibroblasts was found to be decreased [8]
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