Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells.
Cannabinoids possess a number of characteristics that make them putative anticancer drugs, and their value as such is currently being explored in a number of clinical studies. To further understand the roles that cannabinoids may have, we performed gene expression profiling in glioma cell lines cultured with cannabidiol (CBD) and/or Δ9-tetrahydrocannabinol (THC), and pursued targets identified by this screening. Results showed that a large number of genes belonging to the heat shock protein (HSP) super-family were up-regulated following treatment, specifically with CBD. Increases were observed both at the gene and protein levels and arose as a consequence of increased generation of ROS by CBD, and correlated with an increase in a number of HSP client proteins. Furthermore, increases impeded the cytotoxic effect of CBD; an effect that was improved by co-culture with pharmacalogical inhibitors of HSPs. Similarly, culturing glioma cells with CBD and HSP inhibitors increased radiosensitivity when compared to CBD-alone. Taken together, these data indicate that the cytotoxic effects of CBD can be diminished by HSPs that indirectly rise as a result of CBD use, and that the inclusion of HSP inhibitors in CBD treatment regimens can enhance the overall effect.
Department of Oncology, Institute of Infection and Immunity, St George's, University of London, London, U.K.
Katherine A
KA
Scott
Department of Oncology, Institute of Infection and Immunity, St George's, University of London, London, U.K.
Jayne L
JL
Dennis
Department of Oncology, Institute of Infection and Immunity, St George's, University of London, London, U.K.
Angus G
AG
Dalgleish
Department of Oncology, Institute of Infection and Immunity, St George's, University of London, London, U.K. w.liu@sgul.ac.uk.
Wai M
WM
Liu
D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics; D002185:Cannabidiol / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology*; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006213:Hallucinogens / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D006213:Hallucinogens; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D002185:Cannabidiol; D013759:Dronabinol
Heat shock proteins; cannabidiol; glioma; reactive oxygen species; tetrahydrocannabinol