Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture.
Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs.
Departments of Pharmacology, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (L.D., L.N., N.S.); Department of Neurosurgery, Alvord Brain Tumor Center, University of Washington, Seattle, Washington (T.O.); and Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington (T.O.).
Liting
L
Deng
Departments of Pharmacology, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (L.D., L.N., N.S.); Department of Neurosurgery, Alvord Brain Tumor Center, University of Washington, Seattle, Washington (T.O.); and Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington (T.O.).
Lindsay
L
Ng
Departments of Pharmacology, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (L.D., L.N., N.S.); Department of Neurosurgery, Alvord Brain Tumor Center, University of Washington, Seattle, Washington (T.O.); and Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington (T.O.).
Tatsuya
T
Ozawa
Departments of Pharmacology, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington (L.D., L.N., N.S.); Department of Neurosurgery, Alvord Brain Tumor Center, University of Washington, Seattle, Washington (T.O.); and Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Seattle, Washington (T.O.) nstella@uw.edu.
Nephi
N
Stella
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002185:Cannabidiol / Q000009:adverse effects* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004357:Drug Synergism; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D002185:Cannabidiol