title: Pterostilbene-induced tumor cytotoxicity: a lysosomal membrane permeabilization-dependent mechanism.
abstract: The phenolic phytoalexin resveratrol is well known for its health-promoting and anticancer properties. Its potential benefits are, however, limited due to its low bioavailability. Pterostilbene, a natural dimethoxylated analog of resveratrol, presents higher anticancer activity than resveratrol. The mechanisms by which this polyphenol acts against cancer cells are, however, unclear. Here, we show that pterostilbene effectively inhibits cancer cell growth and stimulates apoptosis and autophagosome accumulation in cancer cells of various origins. However, these mechanisms are not determinant in cell demise. Pterostilbene promotes cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 (HSP70) content, a known stabilizer of lysosomal membranes. A375 melanoma and A549 lung cancer cells with low levels of HSP70 showed high susceptibility to pterostilbene, whereas HT29 colon and MCF7 breast cancer cells with higher levels of HSP70 were more resistant. Inhibition of HSP70 expression increased susceptibility of HT29 colon and MCF7 breast cancer cells to pterostilbene. Our data indicate that lysosomal membrane permeabilization is the main cell death pathway triggered by pterostilbene.
authors.affiliation: Green Molecular, Valencia, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Mena
authors.forename: María L
authors.initials: ML
authors.lastname: Rodríguez
authors.forename: Xavier
authors.initials: X
authors.lastname: Ponsoda
authors.forename: José M
authors.initials: JM
authors.lastname: Estrela
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättela
authors.forename: Angel L
authors.initials: AL
authors.lastname: Ortega
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy*; D010539:Permeability; D010588:Phagosomes / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D013267:Stilbenes; C107773:pterostilbene; D007770:L-Lactate Dehydrogenase; D020169:Caspases; D000077185:Resveratrol