Abstract
Brusatol (Bru), a Chinese herbal extract, has a variety of anti-tumor effects. However, little is known regarding its role and underlying mechanism in glioblastoma cells. Here, we found that Bru could inhibit the proliferation of glioblastoma cells in vivo and in vitro. Besides, it also had an inhibitory effect on human primary glioblastoma cells. RNA-seq analysis indicated that Bru possibly achieved these effects through inhibiting the expression of extracellular matrix protein 1 (ECM1). Down-regulating the expression of ECM1 via transfecting siRNA could weaken the proliferation and invasion of glioblastoma cells and promote the inhibitory effect of Bru treatment. Lentivirus-mediated overexpression of ECM1 could effectively reverse this weakening effect. Our findings indicated that Bru could inhibit the proliferation and invasion of glioblastoma cells by suppressing the expression of ECM1, and Bru might be a novel effective anticancer drug for glioblastoma cells.
Highlights
Glioblastoma multiforme (GBM) is the most common primary intracranial malignant tumor, accounting for 48–60% of intracranial tumors in clinical practice (Keles and Berger, 2004; Wen and Kesari, 2008)
Bru could exert its inhibitory effect on human primary GBM cells. These results suggest that Bru is a promising chemotherapeutic drug that is highly effective against glioblastoma cells
Representative images of xenograft tumors from nude mice were shown in Panel (D). (E) Assessment of the tumor growth curves in nude mice after Bru treatment. (F) The weight of xenograft tumors from nude mice were shown in Panel (F). *p < 0.05, **p < 0.01, ***p < 0.001 vs, 0 nM group or Control group
Summary
Glioblastoma multiforme (GBM) is the most common primary intracranial malignant tumor, accounting for 48–60% of intracranial tumors in clinical practice (Keles and Berger, 2004; Wen and Kesari, 2008). Temozolomide (TMZ), the first choice for GBM treatment, only slightly improves the median overall survival (MOS) of these patients. In comparison with patients treated with postoperative radiotherapy alone, the MOS of patients treated with postoperative radiotherapy combined with TMZ was only prolonged by 5 months (McAleenan et al, 2021). The effectiveness of TMZ is significantly limited by the methylation of O6-methylguanine DNA methyltransferase (MGMT) gene promoter. TMZ triggers cytotoxicity increase and cell apoptosis of GBM tumor cells by alkylating the O6-position of guanine, while MGMT is the protein that allows DNA repair by removing the alkyl group from the O6-position of guanine and eventually results in tumor resistance to alkylating agents. Not all GBM patients can benefit from TMZ treatment (Hegi et al, 2019), especially for those patients without MGMT promoter methylation.
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