Pterostilbene and 3'-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells.
Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of trans-resveratrol and piceatannol, two compounds which can induce apoptosis in tumor cells. In previous studies we demonstrated the importance of a 3,5-dimethoxy motif in conferring pro-apoptotic activity to stilbene based compounds so we now wanted to evaluate the ability of pterostilbene and 3,5-hydroxypterostilbene in inducing apoptosis in sensitive and resistant leukemia cells. When tested in sensitive cell lines, HL60 and HUT78, 3'-hydroxypterostilbene was 50-97 times more potent than trans-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not trans-resveratrol and piceatannol, were able to induce apoptosis in the two Fas-ligand resistant lymphoma cell lines, HUT78B1 and HUT78B3, and the multi drug-resistant leukemia cell lines HL60-R and K562-ADR (a Bcr-Abl-expressing cell line resistant to imatinib mesylate). Of note, pterostilbene-induced apoptosis was not inhibited by the pancaspase-inhibitor Z-VAD-fmk, suggesting that this compound acts through a caspase-independent pathway. On the contrary, 3'-hydroxypterostilbene seemed to trigger apoptosis through the intrinsic apoptotic pathway: indeed, it caused a marked disruption of the mitochondrial membrane potential delta psi and its apoptotic effects were inhibited by Z-VAD-fmk and the caspase-9-inhibitor Z-LEHD-fmk. Moreover, pterostilbene and 3'-hydroxypterostilbene, when used at concentrations that elicit significant apoptotic effects in tumor cell lines, did not show any cytotoxicity in normal hemopoietic stem cells. In conclusion, our data show that pterostilbene and particularly 3'-hydroxypterostilbene are interesting antitumor natural compounds that may be useful in the treatment of resistant hematological malignancies, including imatinib, non-responsive neoplasms.
Tolomeo
Manlio
M
Dipartimento di Ematologia, Policlinico, Università di Palermo, via del Vespro 129, 90127 Palermo, Italy. mt4536@policlinico.pa.it
Grimaudo
Stefania
S
Di Cristina
Antonietta
A
Roberti
Marinella
M
Pizzirani
Daniela
D
Meli
Maria
M
Dusonchet
Luisa
L
Gebbia
Nicola
N
Abbadessa
Vincenzo
V
Crosta
Lucia
L
Barucchello
Riccardo
R
Grisolia
Giuseppina
G
Invidiata
Francesco
F
Simoni
Daniele
D
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019450:Genes, MDR; D016313:Genes, abl; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D010636:Phenols / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
C505072:3'-hydroxypterostilbene; D010636:Phenols; D013267:Stilbenes; D019014:fas Receptor; C107773:pterostilbene