Anticancer potential of nerolidol on acute lymphoblastic leukemia cells through the interactions with the NF-κB/STAT-3 and PI3K/Akt signaling pathways

Background: Leukemia may form at any age, from newborns to the elderly, and accounts for considerable mortality worldwide.

Objectives: Nerolidol (NRD) is isolated from the aromatic florae oils and was found to have anticancer activities. However, the role of NRD in antiproliferative and apoptosis actions in acute lymphoblastic leukemia (ALL) is unclear.

Material and methods: Human ALL cell lines, MOLT-4, were used to examine the potential anticancer mechanisms of NRD on cellular proliferation, reactive oxygen species (ROS)-mediated apoptosis, oxidative stress markers, caspases, PI3K/AKT, nuclear factor kappa B (NF-κB), and STAT-3/VEGF/Bcl-2 signaling pathways.

Results: The MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay demonstrated that NRD inhibited MOLT-4 cell proliferation in a concentration-dependent manner, with an IC50 value of 30 μM. It was found that NRD (20 and 30 μM/mL) resulted in accumulated intracellular ROS, reduced oxidative stress and loss of mitochondrial membrane potential (MMP) in MOLT-4 cells in a concentration-related way. Nerolidol was able to induce apoptosis, as evidenced by dual acridine orange/ethidium bromide (AO/EB) staining. The levels of antioxidants, caspases-3, -8 and -9 were enhanced by NRD. This research proves that NRD instantaneously triggers ROS-mediated pro-apoptotic signaling and caspases and attenuates PI3K/Akt/NF-κB and STAT3/VEGF/Bcl-2 anti-apoptotic signaling.

Conclusions: Our results suggest that NRD treatment stimulates apoptosis in MOLT-4 cells by causing the accumulation of intracellular ROS through PI3K/AKT/STAT-3 signaling pathways.