Attenuation of malignant phenotype of glioblastoma following a short course of the pro-oxidant combination of Resveratrol and Copper.

Background: We investigated a novel therapeutic approach to glioblastoma (GBM) that targets cell-free chromatin particles (cfChPs) that are released from dying GBM cells and aggravate the oncogenic phenotype of living GBM cells. cfChPs can be deactivated by oxygen radicals (OR) generated upon oral administration of the nutraceuticals Resveratrol (R) and Copper (Cu).

Methods: Ten patients with glioblastoma awaiting surgery were administered 5.6 mg of Resveratrol (R) and 560 ng of Copper (Cu) four times a day for an average of 11.6 ± 5.37 days. Another ten patients who did not receive R-Cu acted as controls. A tissue sample was taken at operation for analysis.

Results: R-Cu treatment led to marked deactivation of cfChPs that were present in the tumour microenvironment, which was accompanied by a highly significant down-regulation in Ki-67, nine hallmarks of cancer, six immune check-points and three stem cell biomarkers as revealed by immuno-fluorescence analysis. Transcriptome sequencing detected marked upregulation of pro-apoptotic and down-regulation of anti-apoptotic genes. Also detected was down-regulation of PVRIG-2P, a homologue of immune checkpoint receptor PVRIG, which is a functional analogue of PD-L1.

Conclusions: These results suggest that a simple, non-toxic and inexpensive combination of the commonly used nutraceuticals Resveratrol and Copper can have a profound effect on the aggressive phenotype of GBM. Further studies are warranted to evaluate whether prolonged treatment with R-Cu might induce the tumours to adopt a benign phenotype.

Trial registration: ClinicalTrials.gov identifier: CTRI/2020/10/028476 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDY2Mzc=&Enc=&userName=Aliasgar ).