Abstract
Demethoxycurcumin (DMC) has anti-glioma effects in vitro and in subcutaneous xenotransplanted tumors. Our previous study confirmed that the molecule also has mild anti-glioma effects on orthotopic glioblastomas in vivo. In this study, we found that DMC-BH, a DMC analogue, exhibited more potent in vitro and in vivo activities than did DMC. DMC-BH was cytotoxic against various glioma cells including SHG-44, C6, U251, U87, A172 and primary glioma cells. DMC-BH activity was characterized by low acute toxicity and an appropriate pharmacokinetic profile. We evaluated the anti-tumor effects of DMC-BH in an ectopic xenograft model, an orthotopic glioblastoma xenograft model and a patient-derived tumor xenograft (PDTX) model. DMC-BH exhibited potent anti-tumor activity in both the ectopic xenograft and PDTX models. Indeed, bioluminescence measurements showed that DMC-BH exerted a significantly greater anti-tumor effect on orthotopic glioma growth than DMC. Immunohistochemical analysis revealed that DMC-BH inhibited expression of Ki67 and increased the incidence of TUNEL-positive cells. Western blotting showed that DMC-BH significantly decreased p-Akt and p-mTOR expression in orthotopic glioma tissues. These results suggest that the DMC analogue DMC-BH has potent anti-tumor properties that warrant further study.
Highlights
Tumors derived from neuroepithelial tissue are collectively referred to as gliomas and account for between 40% and 50% of brain tumors [1]
We found that DMC does not effectively pass through the blood-brain barrier (BBB) or exert anti-glioma effects in an orthotopic glioblastoma xenograft model
Using bioluminescent imaging (BLI), we found that the inhibitory effect of DMC-BH on orthotopic glioblastomas is significantly higher than that of DMC, which was confirmed by immunohistochemical studies
Summary
Tumors derived from neuroepithelial tissue are collectively referred to as gliomas and account for between 40% and 50% of brain tumors [1]. Malignant glioma is one of the most common intracranial primary tumors, and it is the second most common malignant tumor in children [2]. In the past 30 years, the incidence of primary malignant brain tumors has been increasing, with an annual growth rate of about 1.2%, in the middle-aged and elderly population [3, 4]. The 5-year survival rate, especially in patients with glioblastoma, is still very low. A prospective database study of glioblastoma patients treated between May 2007 and December 2014 found that the median survival time was 17.0 months (95% CI: 15.4-18.6) [5]
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