TY - JOUR
T1 - Pterostilbene and 3'-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells
AU - Dusonchet, Luisa
AU - Gebbia, Nicolo'
AU - Abbadessa, Vincenzo
AU - Grimaudo, Stefania
AU - Meli, Maria
AU - Gebbia, Nicola
AU - Grisolia, Giuseppina
AU - Pizzirani, Daniela
AU - Crosta, Lucia
AU - Simoni, Daniele
AU - Roberti, Marinella
AU - Barucchello, Riccardo
AU - Di Cristina, Antonietta
AU - Invidiata, Francesco
AU - Crosta, Lucia
PY - 2005
Y1 - 2005
N2 - Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of traps-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 traps-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not traps-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 A P and its apoptotic effects were inhibited by Z-VAD-fmk and the caspase-9-inhibitor Z-LEND-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.
AB - Pterostilbene and 3,5-hydroxypterostilbene are the natural 3,5-dimethoxy analogs of traps-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 traps-resveratrol in inducing apoptosis, while pterostilbene appeared barely active. However, both compounds, but not traps-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 A P and its apoptotic effects were inhibited by Z-VAD-fmk and the caspase-9-inhibitor Z-LEND-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.
KW - BCR-ABL
KW - apoptosis
KW - leukemia
KW - multidrug resistance
KW - stilbenes
KW - BCR-ABL
KW - apoptosis
KW - leukemia
KW - multidrug resistance
KW - stilbenes
UR - http://hdl.handle.net/10447/29526
M3 - Article
VL - 37
SP - 1709
EP - 1726
JO - THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
JF - THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
SN - 1357-2725
ER -