Pterostilbene Simultaneously Induced G0/G1-Phase Arrest and MAPK-Mediated Mitochondrial-Derived Apoptosis in Human Acute Myeloid Leukemia Cell Lines

Abstract

BackgroundPterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated.Methodology and Principal FindingsResults showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B.ConclusionTaken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.

Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells

“…First, we demonstrated that pterostilbene showed a dose-dependent cytotoxic effect on six human DLBCL cell lines, OCI-LY8, SUDHL-4, DB, TMD8, U2932, and NU-DUL-1 (Fig. 1A) with an approximate IC 50 of 30 μM after 48 h. Pterostilbene-induced cell proliferation, in a concentration-dependent fashion, has also been observed in other hematological malignancies, including acute myeloid leukemia (AML)14 and MOLT4 human lymphoblastic leukemia32. In addition, we also found that pterostilbene-induced cell viability was not inhibited in a time-dependent manner in three DLBCL cell lines (SUDHL-4, DB and NU-DUL-1) within the setting concentration range.…”

“…4A, the result indicates that pterostilbene was capable of disrupting the MMP and, thus, of activating the intrinsic apoptosis pathway. Moreover, previous studies have reported that oxidative stress induced by pterostilbene originates from increasing levels of reactive oxygen species (ROS) in HL-60 cells14 and breast cancer cells13, and ROS are principal mediators of the ROS-dependent MMP apoptosis pathway. To investigate whether pterostilbene induces intracellular oxidation, we evaluated ROS levels in treated four DLBCL cell lines by flow cytometry using the specific oxidation-sensitive fluorescent dyes DCFH-DA.…”

“…In recent years, the anticarcinogenic effects of pterostilbene have gained increasing attention from many researchers. Several studies have shown that pterostilbene exerts antiproliferative and apoptosis-inducing effects in both solid (such as liver, colon, prostate and breast cancers)10111213 and non-solid tumors (such as acute/chronic myelogenous leukemia and lymphoblastic leukemia)141516. Tolomeo and colleagues16 discovered that pterostilbene induced apoptosis in sensitive and multi-drug resistant leukemia cell lines in vitro .…”

The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells

“…Studies have shown that the MAPK signaling pathway (especially c-jun N-terminal kinase (jNK) and p38 MAPK) is essential for Pter-mediated activation of caspases (21). Another study has reported that a potent pan-PI3K/Akt inhibitor enhances the apoptotic effects of bortezomib in bortezomibresistant cells significantly, suggesting the roles of these signaling pathways in Pter-induced apoptosis (22).…”

Pterostilbene as treatment for severe acute pancreatitis

“…Pterostilbene [(E)-3,5-dimethyl-4-hydroxyl phenyl ethylene] is a 3,5-dimethyl derivative of resveratrol. It is one among the non-flavonoid polyphenol compounds that are found in grapes, nuts, strawberry, Guangxi dragon's blood, and propolia (Hsiao et al, 2014;Sato et al, 2014). Pterostilbene has activities that are similar to those of resveratrol, and shows multiple activities including antifungal, antiproliferative, antioxidant, anti-inflammatory, and antilipidemic activities.…”