Flubendazole elicits anti‐metastatic effects in triple‐negative breast cancer via STAT3 inhibition

Abstract

Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24 /CD44 , CD24 /CD49f subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse. 34,[47][48][49][50] Cells undergoing EMT are known to acquire stem cell-like properties. Loss of epithelial marker E-cadherin, increased expression of mesenchymal markers Fibronectin and Vimentin and the EMT regulator Snail, which are important events in EMT.…”

A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment

“…The canonical activity of STAT3 is mainly dependent on the Janus kinase (JAK) phosphorylation at tyrosine 705 (Y705) [37]. The canonically activated pY705 STAT3 is nuclear targeted and associates with the promoters of early response genes to: promote proliferation, enhance tissue invasion and metastasis (e.g., cyclin D1 and matrix metalloproteinase-2/-9 in breast cancer) [38][39][40][41], activate terminal differentiation and growth arrest, promote evasion of the immune response by suppressing apoptosis [42], promoting angiogenesis, as well as modification of cellular energy metabolism and mitochondrial activity [43,44]. The activation may induce lysosome-mediated apoptosis depending on cell type and conditions or stimulation [45].…”

“…These elevated ROS levels can promote tumourigenesis through destabilizing the genome and increasing ROS dependence in signalling pathways [127][128][129]. Despite cancer cells producing the bulk of ATP through the Warburg effect, the mitochondria are still active and contribute to ROS production through OXPHOS [40,41,130,131], and maintenance of Ca 2+ homeostasis [132][133][134][135][136][137]. Myeloid progenitors produce a much higher ROS than leukocytes produced in mammalian hematopoietic systems.…”

Ilamycin C induces apoptosis and inhibits migration and invasion in triple-negative breast cancer by suppressing IL-6/STAT3 pathway

“…Ilamycin C suppresses the IL-6/STAT3 pathway in TNBC cells Recent studies showed that activated STAT proteins, especially STAT3, are involved in the progression of many malignant tumors [31]. The suppression of phosphorylated STAT3 (p-STAT3) can induce apoptosis and inhibit metastasis in cancer [32,33]. In TNBC, poor prognosis and chemotherapy resistance are related to the activation of STAT3 [34].…”