Ribosome biogenesis mediates antitumor activity of flavopiridol in CD44+/CD24‑ breast cancer stem cells

Abstract

Flavopiridol is a synthetically produced flavonoid that potently inhibits the proliferation of human tumor cell lines. Flavopiridol exerts strong antitumor activity via several mechanisms, including the induction of cell cycle arrest and apoptosis, and the modulation of transcriptional regulation. The aim of the present study was to determine the effect of flavopiridol on a subpopulation of cluster of differentiation (CD)44+/CD24− human breast cancer MCF7 stem cells. The CD44+/CD24− cells were isolated from the MCF7 cell line by fluorescence-activated cell sorting and treated with 100, 300, 500, 750 and 1,000 nM flavopiridol for 24, 48 and 72 h. Cell viability and proliferation assays were performed to determine the inhibitory effect of flavopiridol. Gene expression profiling was analyzed using Illumina Human HT-12 v4 Expression BeadChip microarray. According to the results, the half maximal inhibitory concentration (IC50) value of flavopiridol was 500 nM in monolayer cells. Flavopiridol induced growth inhibition and cytotoxicity in breast cancer stem cells (BCSCs) at the IC50 dose. The present study revealed several differentially regulated genes between flavopiridol-treated and untreated cells. The result of the pathway analysis revealed that flavopiridol serves an important role in translation, the ribosome biogenesis pathway, oxidative phosphorylation, the electron transport chain pathway, carbon metabolism and cell cycle. A notable result from the present study is that ribosome-associated gene expression is significantly affected by flavopiridol treatment. The data of the present study indicate that flavopiridol exhibits antitumor activity against CD44+/CD24− MCF7 BCSCs through different mechanisms, mainly by inhibiting translation and the ribosome biogenesis pathway, and could be an effective chemotherapeutic molecule to target and kill BCSCs.

The nucleolus: a central response hub for the stressors that drive cancer progression

“…This causes cells to become vulnerable to selective inhibition of rRNA synthesis. Many of the chemotherapeutic agents used in the clinic today, including cisplatin, doxorubicin and flavopiridol, mediate their therapeutic effects, at least in part, through the disruption of ribosome biogenesis [131–133].…”

Identification of Genes Regulating Breast Cancer Dormancy in 3D Bone Endosteal Niche Cultures

“…Loss of differentiation (neurogenesis) or stem cell induction genes resulting in active BrCa cell growth in the 3D-EN is consistent with the notion that disseminated tumor cells exhibit stem cell-like properties (28, 29). Differential expression of genes controlling ribosome biogenesis are known to control stem cell homeostasis (30), and indeed, antagonism of this process was shown to inhibit tumor formation induced by CD44 + /CD24 − human BrCa stem cells (31).…”

Flavopiridol's effects on metastasis in KRAS mutant lung adenocarcinoma cells

“…Bible et al demonstrated that flavopiridol caused cell cycle arrest at G1 and G2 phases and inhibited CDK2, CDK4, and CDK1 in NSCLC. 21 In addition to this, the IC 50 dose of flavopiridol was determined as 676 nM for CD133+/CD44+ squamous cell lung cancer cells. 8,20 Similar results were observed in HCT8 ileocecal adenocarcinoma, T98G glioblastoma, MCF7 breast adenocarcinoma, and HL60 leukemia cells.…”

“…Similar results were observed in HCT8 ileocecal adenocarcinoma, T98G glioblastoma, MCF7 breast adenocarcinoma, and HL60 leukemia cells . Erol et al showed that the IC 50 dose of flavopiridol was 500 nM for MCF7 cells and it exhibited antitumoral effects on CD44+/CD24− MCF7 cells at the IC 50 dose by inhibiting translation and the ribosome biogenesis pathway . In addition to this, the IC 50 dose of flavopiridol was determined as 676 nM for CD133+/CD44+ squamous cell lung cancer cells.…”