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

BackgroundWe 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 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. Patients and MethodsTen patients with glioblastoma awaiting surgery were administered tablets containing 5.6mg of Resveratrol (R) and 560ng 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 biopsy of the tumour tissues was taken at operation for analysis using confocal microscopy, immunofluorescence and transcriptome sequencing. ResultsConfocal 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. ConclusionThe results of our study suggest that oral administration of a non-toxic combination of small quantities of the commonly used nutraceuticals R and Cu can have a profound effect in attenuating the aggressive phenotype of GBM. They also suggest that cfChPs are the key activators of cancer hallmarks, immune checkpoints and cancer stemness in GBM. Further studies are required to investigate whether prolonged treatment with R-Cu may induce the tumour to adopt a benign phenotype. Trial registrationClinicalTrials.gov identifier: CTRI/2020/10/028476 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDY2Mzc=&Enc=&userName=Al iasgar) Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=141 HEIGHT=200 SRC="FIGDIR/small/25322384v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@c1a3b4org.highwire.dtl.DTLVardef@e28704org.highwire.dtl.DTLVardef@e245forg.highwire.dtl.DTLVardef@75f9d3_HPS_FORMAT_FIGEXP M_FIG C_FIG Attenuation of malignant phenotype of glioblastoma by oxygen radicals (ROS) generated by combining Resveratrol and Copper.