TY - JOUR

T1 - Pterostilbene-induced tumor cytotoxicity

T2 - a lysosomal membrane permeabilization-dependent mechanism

AU - Mena, Salvador

AU - Rodríguez, María L

AU - Ponsoda, Xavier

AU - Estrela, José M

AU - Jaattela, Marja

AU - Ortega, Angel L

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Antineoplastic Agents

KW - Apoptosis

KW - Autophagy

KW - Caspases

KW - Cell Death

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Dose-Response Relationship, Drug

KW - Flow Cytometry

KW - HSP70 Heat-Shock Proteins

KW - Humans

KW - Inhibitory Concentration 50

KW - L-Lactate Dehydrogenase

KW - Lysosomes

KW - Microscopy, Confocal

KW - Necrosis

KW - Neoplasms

KW - Permeability

KW - Phagosomes

KW - Stilbenes

U2 - 10.1371/journal.pone.0044524

DO - 10.1371/journal.pone.0044524

M3 - Journal article

C2 - 22957077

VL - 7

SP - e44524

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

ER -