Entry #: 5 Date: 7 July 2017
Section: Phenolic compounds
Topic: Oleocanthal and Lysosomal degradation in cancer
Type: Molecular mechanism

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OliveNetTM Journal Club

Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis

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

Author(s)

Le Gendre O, Breslin PAS, and Foster DA.

Citation / Year

(1) / 2015

Keywords

oleocanthal, cell-death, necrosis, apoptosis, cell cycle arrest, lysosomal membrane permeabilization

Summary

Following the initial isolation, characterization and synthesis of oleocanthal, a phenolic secoiridoid of extra-virgin olive oil (2), a plethora of studies have investigated the biological effects of the compound. Apart from anti-inflammatory effects via potent inhibition of COX-1 and COX-2 enzymes, oleocanthal has been shown to: 1) possess neuroprotective effects including modulation of tau and β-amyloid neurotoxicity and aggregation in models of Alzheimer’s disease (3, 4), and 2) induce cell-death, apoptosis and inhibit proliferation and migration in cancer cells [for example (5)]. In this study, the effects of oleocanthal in human cancer cell lines were investigated. Specifically, the authors utilised prostate (PC3 cells), MDA-MB-231 (breast) and BxPC3 (pancreatic) cancer cells to investigate the mechanisms of oleocanthal-induced cell-death. The findings indicated rapid (30 min) loss of cell viability in cancer cells following treatment with 20 μM oleocanthal in serum-free conditions; 100% loss of viability in all cancer cell lines after 24 hours. By analysing the effects of oleocanthal on cleavage of poly-ADP-ribose polymerase (PARP) and caspase-3 (indicators of apoptotic cell-death), the authors concluded that necrotic cell-death was the primary mode in serum-free conditions. In the presence of serum, oleocanthal increased levels of cleaved PARP and caspase-3 indicating activation of apoptosis. Overall, the data indicate robust induction of cell-death with differential mechanisms in serum and serum-free media. Importantly, by utilising primary fibroblasts the findings indicated that oleocanthal, reduced proliferation but did not induce-cytotoxicity in the normal cells. The data indicate that oleocanthal induces reversible cell cycle arrest in the normal cells; proliferation restored after 72 hours in the presence of serum. The mechanism was found to be, at least in part, due to inhibition of phosphorylation of the retinoblastoma protein (phospho-RB [Ser608]) by oleocanthal.

Key points and implications

Previous studies have indicated that oleocanthal possesses potential anti-cancer effects by a number of different molecular mechanisms including: 1) inhibition of tyrosine-protein kinase Met (c-Met) or hepatocyte growth factor receptor resulting in attenuation of proliferation, migration and invasion of breast and prostate cancer cells (6), 2) inhibition of 5′ adenosine monophosphate-activated protein kinase (AMPK) in colon cancer cells (7), and 3) inhibition of macrophage inflammatory protein-1β in multiple myeloma (8). This study extends the mechanisms of cancer cell-death induced by oleocanthal. The findings indicate that oleocanthal preferentially induces cell-death in cancer cells by downregulating lysosomal acid spingomyelinase (ASM) leading to lysosomal membrane permeabilization. Interestingly, the effects of oleocanthal were attenuated by treatment Hsp70 and anionic free fatty acids, which stabilize the lysosomal membrane. As noted by the authors, the specificity for cell-death induction in malignant cells by oleocanthal may be due to the fact that lysosomes are enlarged and have greater cathepsin activity in cancer compared to normal cells (9, 10). Overall, this study highlights the potential utility of oleocanthal, and more generally of lysomotropic agents, as anticancer agents.

Related publications

  1. O. LeGendre, P. A. Breslin, D. A. Foster, (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization. Mol Cell Oncol 2, e1006077 (2015).
  2. G. K. Beauchamp et al., Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature 437, 45-46 (2005).
  3. A. H. Abuznait, H. Qosa, B. A. Busnena, K. A. El Sayed, A. Kaddoumi, Olive-oil-derived oleocanthal enhances beta-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: in vitro and in vivo studies. ACS Chem Neurosci 4, 973-982 (2013).
  4. W. Li et al., Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 110, 1339-1351 (2009).
  5. J. A. Menendez et al., Olive oil’s bitter principle reverses acquired autoresistance to trastuzumab (Herceptin) in HER2-overexpressing breast cancer cells. BMC Cancer 7, 80 (2007).
  6. A. Y. Elnagar, P. W. Sylvester, K. A. El Sayed, (-)-Oleocanthal as a c-Met inhibitor for the control of metastatic breast and prostate cancers. Planta Med 77, 1013-1019 (2011).
  7. P. Khanal et al., p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP-activated protein kinase to inhibit carcinogenesis. Carcinogenesis 32, 545-553 (2011).
  8. M. Scotece et al., Oleocanthal inhibits proliferation and MIP-1alpha expression in human multiple myeloma cells. Curr Med Chem 20, 2467-2475 (2013).
  9. J. Nylandsted et al., Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200, 425-435 (2004).
  10. M. M. Mohamed, B. F. Sloane, Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6, 764-775 (2006).

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