title: Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma.
abstract: Increased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Issan
authors.initials: I
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Abdolali
authors.initials: A
authors.lastname: Amiri
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada.
authors.forename: Yidan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Campbell
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. Electronic address: dusica.maysinger@mcgill.ca.
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects* / Q000378:metabolism*; D008969:Molecular Sequence Data; D016896:Treatment Outcome
chemical_list: D003474:Curcumin
keywords: Caspase-3 sensor; Cell death; Chemotherapy; Curcumin; Glioblastoma; Lipid droplets; Pyrrolidine-2; Sensitization; Spheroids; Temozolomide