Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Abstract

a b s t r a c tIncreased 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.

Inhibition of carbonic anhydrase IX in glioblastoma multiforme

“…We detected picnotic nuclei and significantly enhanced caspase-3 activity, indicative of apoptotic cell death. We have previously shown that in transfected glioblastoma cells, curcumin but not TMZ, causes a significant activation of caspase-3 [59]. In the present study, it is worth noting that the increase in caspase-3 activity with the combined treatment in comparison with the untreated controls was markedly higher in the 2D monolayers relative to the 3D spheroids, apparently more resistant to the anticancer treatment [44].…”

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

“…A separate, intriguing method by which GBM may resist hydrophobic therapeutic agents is by accumulating lipid droplets that sequester these drugs. Curcumin is hydrophobic and has been shown to concentrate near the cell membrane and in cytoplasmic droplets of U251N human GBM cells [61]. Zhang et al sought to overcome this mechanism of resistance in vitro using pyrrolidine-2, a cytoplasmic phospholipase A2 α inhibitor, in combination with curcumin.…”

“…Zhang et al sought to overcome this mechanism of resistance in vitro using pyrrolidine-2, a cytoplasmic phospholipase A2 α inhibitor, in combination with curcumin. When the cells were pretreated with pyrrolidine-2 24 hours before curcumin administration, cell viability was found to approach 0% [61]. …”

Aberrant lipid metabolism as an emerging therapeutic strategy to target cancer stem cells

“…The effects of curcumin and berberine in exerting anti-tumorigenic effects in glioblastoma multiforme and breast cancer have been demonstrated to act via inhibiting LD accumulation. 75,76 In breast cancer, there was also an observed downregulation in expression of stemness genes such as ALDH1A3, CD49f, PROM1, and TP63, facilitated via the blockade of SCD1 by curcumin. 69 It was demonstrated that SCD1 inhibitors CAY10566 and SC-26196 block conversion of saturated FAs to MUFA by inhibiting SCD1 and Δ6, respectively.…”