The Cardiac Glycoside Deslanoside Exerts Anticancer Activity in Prostate Cancer Cells by Modulating Multiple Signaling Pathways

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (ITG2B, CNIH2, FBF1, PABPC1L, MMP11, DUSP9, TMEM121, SOX18, CMPK2, and MAMDC4) inversely correlated, while one deslanoside-upregulated gene (RASD1) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (ENG) inversely correlated, while three upregulated genes (JUN, MXD1, and AQP3) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.

Nur77 Serves as a Potential Prognostic Biomarker That Correlates with Immune Infiltration and May Act as a Good Target for Prostate adenocarcinoma

“…It has been reported that cardenolide glycosides have a dramatic anti-cancer role in diverse types of human cancers, such as PRAD [ 49 , 50 ]. The anti-cancer effect of cardenolide glycosides was associated with a variety of proteins and signaling pathways [ 51 , 52 , 53 ]. In the present study, malayoside was found to be critical to the suppression of the growth ( Figure 4 B) and induction of apoptosis ( Figure 4 C–H) in PRAD cells.…”

Nitazoxanide inhibits acetylated KLF5-induced bone metastasis by modulating KLF5 function in prostate cancer

“…Extraction of RNA, construction of libraries using the SE100 protocol, and sequencing with a DNBSEQ platform with pair-end 100 bp sequencing length were performed by the Beijing Genomics Institute (Wuhan, China). Raw data processing was completed as previously described [14]. All RNA-seq data were processed by FASTQC for quality assessment and aligned to the human genome using Bowtie2 (V2.2.5) [27].…”

“…TGF-β plays a pivotal role in the development of bone metastasis, even though it suppresses cell proliferation and tumor growth in the early stages of tumorigenesis [8][9][10][11]. Although the TGF-β signaling is an attractive target for treating bone metastasis, directly targeting TGF-β and its receptors have proven challenging for different reasons [12][13][14]. For example, TGF-β has critical functions in tissue homeostasis [14], and TGF-β-targeting compounds are often not selective and thus could cause toxicities to cardiac tissues and skin [15,16].…”

Necroptosis and Prostate Cancer: Molecular Mechanisms and Therapeutic Potential

“…Anticancer effects of cardiac glycoside deslanoside, which is found in the leaves of Digitalis lanata , were reported in PCa cell lines ( Figure 2 and Table 2 ) [ 55 ]. This drug shows in vitro antiproliferative activity and tumor growth inhibition in vivo on 22Rv1, PC3, and DU145 cells.…”