Phenethyl isothiocyanate exhibits antileukemic activity in vitro and in vivo by inactivation of Akt and activation of JNK pathways

Abstract

Effects of phenethyl isothiocyanate (PEITC) have been investigated in human leukemia cells (U937, Jurkat, and HL-60) as well as in primary human acute myeloid leukemia (AML) cells in relation to apoptosis and cell signaling events. Exposure of cells to PEITC resulted in pronounced increase in the activation of caspase-3, -8, -9, cleavage/degradation of PARP, and apoptosis in dose- and time-dependent manners. These events were accompanied by the caspase-independent downregulation of Mcl-1, inactivation of Akt, as well as activation of Jun N-terminal kinase (JNK). Inhibition of PI3K/Akt by LY294002 significantly enhanced PEITC-induced apoptosis. Conversely, enforced activation of Akt by a constitutively active Akt construct markedly abrogated PEITC-mediated JNK activation, Mcl-1 downregulation, caspase activation, and apoptosis, and also interruption of the JNK pathway by pharmacological or genetically (e.g., siRNA) attenuated PEITC-induced apoptosis. Finally, administration of PEITC markedly inhibited tumor growth and induced apoptosis in U937 xenograft model in association with inactivation of Akt, activation of JNK, as well as downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Akt/JNK/Mcl-1 pathway potentiate PEITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of U937 xenograft model.

Baicalin Augments Hyperthermia-Induced Apoptosis in U937 Cells and Modulates the MAPK Pathway via ROS Generation

“…Its phosphorylation at Thr 308 increases its activity while its phosphorylation at Ser 473 is required for its full activation, which eventually suppresses various proapoptotic signaling molecules involved in cell growth and proliferation [52]. Activation of JNK usually occurs from the activation of ASK1, which is a target of Akt inhibitory phosphorylation, and provides the direct link between Akt and JNK [34, 53, 54]. Sometimes induction of apoptosis is done by following the pathway of RAF1-ERK or ASK1-JNK signals, especially in the presence of any kind of stress [30].…”

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

“…Studies have confirmed that the activation of CREB is positively regulated through Akt [48][49][50][51][52] . Akt plays important roles in preventing cell apoptosis [53] . The activity of JNK is negatively regulated through Akt, whereas JNK activation is involved in the mitochondria-mediated apoptosis pathway [42,43] .…”

Inhibition of Mitochondrial Respiration and Rapid Depletion of Mitochondrial Glutathione by β-Phenethyl Isothiocyanate: Mechanisms for Anti-Leukemia Activity

“…PEITC effectively kills various cancer cells with low toxicity to normal cells (16,36,44,46), suggesting that this compound may have a promising therapeutic potential due to its potent anticancer activity and selectivity. One likely mechanism that contributes to the anticancer selective of PEITC is the ability of this compound to disable the cellular GSH antioxidant system through depletion of GSH and inhibition of GPX enzyme activity (36,46).…”