trans-4,4’-Dihydroxystilbene (DHS) inhibits human neuroblastoma tumor growth and induces mitochondrial and lysosomal damages in neuroblastoma cell lines
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Bhaskar Saha1,2,*, Birija Sankar Patro3,4,*, Mrunesh Koli3, Ganesh Pai3, Jharna Ray2, Sandip K. Bandyopadhyay1 and Subrata Chattopadhyay3,4
1Vijaygarh Jyotish Ray College, Jadavpur, Kolkata 700 032, India
2S. N. Pradhan Centre for Neuroscience, Ballygunge Science College, University of Calcutta, Kolkata 700 019, India
3Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India
4Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India
*These authors have contributed equally to this work
Subrata Chattopadhyay, email: [email protected]
Keywords: apoptosis, trans-4,4’-dihydroxystilbene, neuroblastoma, lysosomal membrane permeabilization, mitochondrial membrane permeabilization
Received: September 09, 2016 Accepted: March 24, 2017 Published: May 16, 2017
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.
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