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. 2017 Jan;360(1):215-224.
doi: 10.1124/jpet.116.236968. Epub 2016 Nov 7.

Quantitative Analyses of Synergistic Responses Between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

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Quantitative Analyses of Synergistic Responses Between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture

Liting Deng et al. J Pharmacol Exp Ther. .
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Abstract

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.

Figures

Fig. 1.
Fig. 1.
CBD inhibits the cell proliferation and viability of GBM cells and NPCs. Dose response of CBD on inhibiting proliferation (A) and viability (B) of (red) human GBM cell lines (T98G, U251, and U87MG) and (blue) mouse PDGF-GBM cells and NPCs at the 72-hour time point. Data are expressed as means ± S.E.M. (n = 5–9 independent experiments, each in triplicate). Vehicle comprised 0.1% dimethylsulfoxide.
Fig. 2.
Fig. 2.
DNA-damaging agents on the proliferation of GBM cells and NPCs: single and CBD combination responses. (A–C) Dose response of TMZ (A), BCNU (B), and CDDP (C) on inhibiting proliferation of (red) human GBM cells (T98G, U251, and U87MG) and (blue) mouse PDGF-GBM cells and NPCs at the 72-hour time point. Data are expressed as means ± S.E.M. (n = 5–9 independent experiments, each in triplicate). Vehicle comprised 0.1% DMSO (A), 0.1% ethanol (B), or 0.1% PBS (C). (D) Interactions between CBD and DNA-damaging agents on inhibiting proliferation (method 1). Percentage of synergy (white), additivity (gray), and antagonism (black) that occurred in the checkerboard assay. Synergy was defined as ΣFIC < 0.5; antagonism was defined as ΣFIC > 4, and additivity was defined as 0.5 < ΣFIC < 4. Data are expressed as percentage of occurrence calculated using the mean ΣFIC from three independent experiments, each in duplicate. Vehicle comprised 0.05% DMSO (vehicle in lieu of CBD) plus 0.05% DMSO, ethanol, or PBS (vehicle in lieu of TMZ, BCNU, or CDDP, respectively). DMSO, dimethylsulfoxide.
Fig. 3.
Fig. 3.
DNA-damaging agents on the cell viability of GBM cells and NPCs: single and CBD combination. (A–C) Dose response of TMZ (A), BCNU (B), and CDDP (C) on inhibiting viability of (red) human GBM cells (T98G, U251, and U87MG) and (blue) mouse PDGF-GBM cells and NPCs at the 72-hour time point. Data are expressed as means ± S.E.M. (n = 5 independent experiments, each in triplicate). Vehicle comprised 0.1% DMSO (A), 0.1% ethanol (B), or 0.1% PBS (C). (D) Interactions between CBD and DNA-damaging agents on inhibiting viability (method 1). Percentage of synergy (white), additivity (gray), and antagonism (black) occurred in the checkerboard assay. Synergy was defined as ΣFIC < 0.5, antagonism was defined as ΣFIC > 4, and additivity was defined as 0.5 < ΣFIC < 4. Data are expressed as percentage of occurrence calculated using the mean ΣFIC from three independent experiments, each in duplicate. Vehicle comprised 0.05% DMSO (vehicle in lieu of CBD) plus 0.05% DMSO, ethanol, or PBS (vehicle in lieu of TMZ, BCNU, or CDDP, respectively). DMSO, dimethylsulfoxide.
Fig. 4.
Fig. 4.
Efficacy FIC analyses on interactive responses between CBD and DNA-damaging agents on GBM cells and NPCs (method 2). (A and B) Efficacy FIC indices calculated from the combinations producing half maximal inhibitory effects on proliferation (A) and viability (B) when DNA-damaging agents were combined with CBD at a fixed concentration of 1 µM. Synergy (white) was defined as an FIC index (ΣFIC) < 0.5, additivity (gray) was defined as 0.5 < ΣFIC < 4, and antagonism (black) was defined as ΣFIC > 4. Data are expressed as means ± S.E.M. (n = 3 independent experiments, each in duplicate). Vehicle comprised 0.05% DMSO (vehicle in lieu of CBD) plus 0.05% DMSO, ethanol, or PBS (vehicle in lieu of TMZ, BCNU, or CDDP, respectively). DMSO, dimethylsulfoxide.

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