A low MW inhibitor of CD44 dimerization for the treatment of glioblastoma

Abstract

Background and Purpose: As a hallmark of glioblastoma multiforme (GBM), CD44 plays a crucial role in promoting glioblastoma stem cell (GSC) stemness phenotypes and multiple drug resistance. The therapeutic potential of CD44 has been validated by the clinical successes of several CD44 inhibitors, including antibodies and hyaluronan-related drugs. Experimental Approach: We used systemsDock software to predict verbascoside as a candidate CD44 inhibitor. Microscale thermophoresis was used to confirm the interaction between CD44 and verbascoside. Four glioblastoma cell lines and a patient-derived glioblastoma cell line were used to test the influences of verbascoside on glioblastoma. CD44-overexpressing and CD44-knockout cell lines were also used. Real-time quantitative PCR and western blot analyses were performed. A xenograft mouse model was used to test verbascoside. Key Results: Verbascoside bound to CD44 and suppressed its dimerization. By inhibiting CD44 dimerization, verbascoside decreased the release of the CD44 intracellular domain (CD44ICD) and suppressed the expression of CD44 downstream genes. Verbascoside treatment suppressed the stemness phenotypes of cells with high CD44 expression. In a mouse model of glioma, verbascoside treatment highly reduced the growth of intracranial tumours and inhibited CD44ICD release. Both stem cell marker and mesenchymal GBM subtype marker genes were downregulated in verbascoside-treated mice. Conclusion and Implications: Verbascoside suppressed growth of glioblastoma cells by inhibiting CD44 dimerization. Stem cell-like cell properties and tumour cell growth were also suppressed by verbascoside, both in vitro and in vivo. Verbascoside significantly prolonged survival of xenografted mice.

Macrophage–stroma interactions in fibrosis: biochemical, biophysical, and cellular perspectives

“…Putative targets and therapeutics to skew profibrotic macrophages to a more pro‐inflammatory phenotype. Antagonists/inhibitors for integrin β1 [175–178], integrin α2 [179,180], CD44 [181] or TRPV4 [87,91,182–184]. Agonist for TLR4 [185–187].…”

Epigenetic Mechanisms Mediating Cell State Transitions in Chondrocytes

“…( 49 ) RNA isolation and Alcian blue (Merck, Darmstadt, Germany) staining ( 50 ) was performed after 4 and 7 days of differentiation. Cells were treated with 120 μM CD44 inhibitor Verbascoside (Taufkirchen, Germany) ( 51 ) during differentiation. Images were taken on a Zeiss Axioplan 2 microscope with a SPOT 14.2 camera and SPOT advanced software (Diagnostic Instruments, Sterling Heights, MI, USA).…”

“…(49) RNA isolation and Alcian blue (Merck, Darmstadt, Germany) staining (50) was performed after 4 and 7 days of differentiation. Cells were treated with 120 μM CD44 inhibitor Verbascoside (Taufkirchen, Germany) (51)…”

Extracellular matrix and its therapeutic potential for cancer treatment

“…However, due to the lack of a comprehensive understanding of all CD44 isoforms and the consequences of knocking down a mixture of CD44 isoforms, some challenges persist for the clinical applications of a siRNA-based strategy targeting CD44. Recently, verbascoside has been identified as small molecular-weight inhibitors for CD44 dimerization, and it showed inhibitory effects on the growth of intracranial tumors in a mouse model of glioma 517 . DNA aptamer targeting the HA-binding domain of CD44 also exhibited suppressive effects on the invasiveness of breast cancer cell line MDA-MB-231 518 .…”