A low MW inhibitor of CD44 dimerization for the treatment of glioblastoma. (5th April 2020) - Wang, Chongwu
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 down‐regulated 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.