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(-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization.

Abstract

(-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been implicated in the health benefits associated with diets rich in EVOO. We investigated the effect of OC on human cancer cell lines in culture and found that OC induced cell death in all cancer cells examined as rapidly as 30 minutes after treatment in the absence of serum. OC treatment of non-transformed cells suppressed their proliferation but did not cause cell death. OC induced both primary necrotic and apoptotic cell death via induction of lysosomal membrane permeabilization (LMP). We provide evidence that OC promotes LMP by inhibiting acid sphingomyelinase (ASM) activity, which destabilizes the interaction between proteins required for lysosomal membrane stability. The data presented here indicate that cancer cells, which tend to have fragile lysosomal membranes compared to non-cancerous cells, are susceptible to cell death induced by lysosomotropic agents. Therefore, targeting lysosomal membrane stability represents a novel approach for the induction of cancer-specific cell death.

Figure 1.

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OC induces loss of cell viability in cancer cells but reversible cell cycle arrest in non-cancerous cells. (A, B) PC3, MDA-MB-231, and BxPC3 cells were plated at a density of 3 × 105 cells/35-mm plate. After 24 h the medium was replaced with fresh medium containing 0% serum (A) or 10% serum (B) and the indicated concentration of OC. After incubation for 4 h, levels of cleaved PARP, phospho-p44/42 (Thr202/Tyr204), total p44/42, cleaved caspase 3, and GAPDH were determined. Cell viability was determined after 24 h of treatment. (C) BJ, 3Y1, and IMR90 cells were plated at a density of 5 × 104 cells/35-mm plate. After 24 h the cells were provided with fresh media containing 10% serum and the indicated concentration of OC or rapamycin (Rapa). After incubation for 24, 48, or 72 h the attached cells were counted to determine cell proliferation. (D) (Upper left panel) BJ cells were plated at a density of 2 × 105 cells/35-mm plate. After 24 h the cells were provided with fresh media containing 10% serum and the indicated concentration of OC. After incubation for 4 h, levels of cleaved PARP, phospho-p44/42 (Thr202/Tyr204), and GAPDH were determined. (Lower left panel) BJ cells were plated at a density of 5 × 104 cells/35-mm plate. After 24 h the cells were provided with fresh media containing 10% serum and the indicated concentration of OC or Rapa. After a further 24, 48, 72, 96, or 120 h, the cells were counted to determine cell proliferation. (Right panel) BJ, 3Y1, and IMR90 cells were plated as above. After 24 h the cells were provided with fresh media containing 10% serum and the indicated concentration of OC or Rapa. After a further 24, 48, or 72 h, the cells were subjected to western blot analysis for phosphorylated Rb (Ser608) and GAPDH or β-actin. Error bars for all graphs represent the standard deviation from two independent experiments. All data shown are representative of at least two independent experiments.

Source: NCBI