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.