Abstract
In view of the inadequacy of neuroblastoma treatment, five hydroxystilbenes and resveratrol (Resv) were screened for their cytotoxic property against human neuroblastoma cell lines. The mechanism of cytotoxic action of the most potent compound, trans-4,4’-dihydroxystilbene (DHS) was investigated in vitro using human neuroblastoma cell lines. DHS was also tested in a mouse xenograft model of human neuroblastoma tumor. The MTT, sub-G1, annexin V and clonogenic assays as well as microscopy established higher cytotoxicity of DHS than Resv to the IMR32 cell line. DHS (20 μM) induced mitochondrial membrane permeabilization (MMP) in the cells, as revealed from JC-1 staining, cytochrome c and ApaF1 release and caspases-9/3 activation. DHS also induced lysosomal membrane permeabilization (LMP) to release cathepsins B, L and D, and the cathepsins inhibitors partially reduced MMP/caspase-3 activation. The ROS, produced by DHS activated the p38 and JNK MAPKs to augment the BAX activity and BID-cleavage, and induce LMP and MMP in the cells. DHS (100 mg/kg) also inhibited human neuroblastoma tumor growth in SCID mice by 51%. Hence, DHS may be a potential chemotherapeutic option against neuroblastoma. The involvement of an independent LMP as well as a partially LMP-dependent MMP by DHS is attractive as it provides options to target both mitochondria and lysosome.
Highlights
Neuroblastoma is the most common solid tumor in children, and a major cause of death from childhood neoplasia
We carried out the clonogenic assay to assess the effect of DHS and Resv on the above neuroblastoma cell lines
Since controlled lysosomal membrane permeabilization (LMP) has emerged as a significant inducer of membrane permeabilization (MMP) and apoptosis [22, 25], we examined if DHS treatment affects lysososmal function/integrity and induces LMP in the IMR32 cells
Summary
Neuroblastoma is the most common solid tumor in children, and a major cause of death from childhood neoplasia. Amplification of the MYCN gene occurs in 40-50% of the high risk neuroblastoma. Patients with high risk neuroblastoma along with MYCN amplification typically show high resistance and poor therapeutic benefits [1,2]. The treatment options against neuroblastoma include chemotherapy either before surgery (neoadjuvant chemotherapy) or after surgery (adjuvant chemotherapy). The prognosis of patients with advanced neuroblastoma is very poor, while majority of the chemotherapeutic agents have side effects and/ or are expensive. There is an urgent need for appropriate drug formulations for the treatment of paediatric malignancies, and the natural polyphenols may be an attractive options for this [4]. Consumption of vegetables and fruit-rich diets www.impactjournals.com/oncotarget is considered to have positive impact against cancer that correlates well with their constituent polyphenolics [5,6]
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