trans-4,4’-Dihydroxystilbene (DHS) inhibits human neuroblastoma tumor growth and induces mitochondrial and lysosomal damages in neuroblastoma cell lines

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.

Gamma linolic acid regulates PHD2 mediated hypoxia and mitochondrial apoptosis in DEN induced Hepatocellular carcinoma

“…Previous published literature in vitro and in vivo studies suggested the anticancer effect of GLA. GLA reduced tumor growth in a WBC256 rat model; it also inhibited the cell growth of various rat carcinogenesis cell lines and human neuroblastoma cell lines 19,20. GLA treatment down-regulated mammary gland carcinogenesis and tumor growth.…”

Anticancer Potential of Resveratrol, β-Lapachone and Their Analogues

“…The pharmacological action of 4,4 -DHS in the human neuroblastoma IMR32 cells was mediated by the destabilization of mitochondrial and lysosomal membranes, associated with modulation of several related pro-and anti-apoptotic cascades of proteins. Additionally, in the animal model, the oral administration of 4,4 -DHS for one month was well tolerated and demonstrated a greater therapeutic potential than resveratrol [56]. More recently, Saha et al demonstrated that in melanoma cells, 4,4 -DHS acts by inducing apoptosis and cell cycle arrest in G1 phase and inhibiting cell proliferation.…”

Therapeutic Versatility of Resveratrol Derivatives

“…4,4′-DHS ( Figure 3 ) in the human neuroblastoma IMR32 cells was shows destabilization of mitochondrial and lysosomal membranes. Its cause lysosomal membrane permeabilization to reduce MMP/caspase-3 activation through the production of cathepsins B, L and D, and the cathepsins [ 88 ].…”