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

Background

We present a novel therapeutic approach to glioblastoma (GBM) that targets cell-free chromatin particles (cfChPs) released from dying GBM cells to aggravate the oncogenic phenotype of bystander living GBM cells. cfChPs can be deactivated by oxygen radicals (OR) generated upon admixing the nutraceuticals Resveratrol (R) and Copper (Cu). Oral administration of R-Cu leads to generation of OR which are readily absorbed to deactivate cfChPs.

Method

Ten patients with glioblastoma awaiting surgery were administered tablets containing 5.6mg of Resveratrol (R) and 560ng of Copper (Cu) q.i.d. for an average of 11.6 ± 5.37 days. Another ten patients who did not receive R-Cu acted as controls. A biopsy of the tumour tissues was taken at operation for analysis using confocal microscopy, immunofluorescence and transcriptome sequencing.

Results

Confocal microscopy of tumour sections revealed copious presence of cfChPs in the tumour microenvironment (TME) that had been released from dying GBM cells. R-Cu treatment led to deactivation / eradication of cfChPs. Eradication of cfChPs from TME led to a highly significantly reduction in Ki-67 and nine hallmarks of cancer, six immune check-points and three stem cell biomarkers. 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.

Conclusion

These results suggest that cfChPs released into TME are global instigators of aggressive phenotype of glioblastoma which can be attenuated by a short course of R-Cu. Trials using long term treatment with R-Cu are warranted.

ClinicalTrials.gov identifier: CTRI/2020/10/028476

Key Points

• Cell-free chromatin from dying GBM cells aggravate oncogenesis in living GBM cells

• Admixing Resveratrol with copper (R-Cu) generates oxygen radicals (OR)

• R-Cu induced OR deactivate cell-free chromatin and abates oncogenesis in GBM cells

Importance of the Study

Glioblastoma (GBM) is an incurable disease and novel therapeutic approaches are needed. Herein we present one such therapeutic approach that is non-toxic and inexpensive and targets cell-free chromatin particles (cfChPs) that are released from dying GBM cells to aggravate the oncogenic phenotype of living GBM cells. cfChPs can be deactivated by oxygen radicals (OR) generated upon combining the nutraceuticals Resveratrol (R) and Copper (Cu). Oral administration of R-Cu leads to generation of OR in the stomach which are readily absorbed to deactivate cfChPs that are released into the tumour microenvironment (TME) of GBM. Pre-operative treatment of patients with R-Cu for ∼11 days led to deactivation / elimination of cfChPs from TME. Elimination of cfChPs from TME led to a highly significantly reduction in Ki-67 and nine hallmarks of cancer, six immune check-points and three stem cell biomarkers. Prolonged treatment with R-Cu may induce GBM cells to adopt a benign phenotype.