Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells

Abstract

Neuroblastoma, a paediatric malignancy of the sympathetic nervous system, accounts for 15 % of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat partly due to the development of multidrug resistance. There is thus a compelling demand for new treatment strategies that can bypass resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various tumour models. We have previously reported that PBOX compounds induce apoptosis in drug sensitive and multidrug resistant neuroblastoma cells and synergistically enhance apoptosis induced by chemotherapeutics such as carboplatin. In this study we present further data concerning the molecular basis of PBOX-induced apoptosis in neuroblastoma. We demonstrate that PBOX-6 induced AMP-activated protein kinase (AMPK) activation and downstream acetyl-CoA carboxylase phosphorylation. Increased reactive oxygen species (ROS) appeared to serve as the upstream signal for AMPK activation as pretreatment of cells with the antioxidant N-acetylcysteine inhibited both AMPK activation and PBOX-induced apoptosis. Furthermore, activation of AMPK by PBOX-6 was found to inhibit mTOR complex 1 (mTORC1) signalling. Finally, we demonstrate the efficacy of PBOX-6 in an in vivo xenograft model of neuroblastoma. This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further supports their future use as novel anti-cancer agents for the treatment of neuroblastoma.

Disruption of the exocyst induces podocyte loss and dysfunction

“…Interestingly, apoptotic nuclei were also observed in cells surrounding the glomeruli. This is not totally surprising given the fact that there is significant cross-talk between podocytes and other glomerular cell types, including endothelial cells and the glomerular basement membrane (39).…”

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents

“…This study presented the PBOX‐6‐induced reactive oxygen species production, which was preceded by PBOX mediation for the first time that activated 5′‐adenosine monophosphate‐activated protein kinase (AMPK) leading to the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. This group also reported that derivative 84 reduces tumor burden in an in vivo neuroblastoma model, indicating that the effects of PBOX‐6 are not limited to cell lines in vitro that provides new information on the molecular and cellular mechanisms in PBOX‐6‐induced cell death in neuroblastoma [81] …”

“…This group also reported that derivative 84 reduces tumor burden in an in vivo neuroblastoma model, indicating that the effects of PBOX-6 are not limited to cell lines in vitro that provides new information on the molecular and cellular mechanisms in PBOX-6-induced cell death in neuroblastoma. [81] Campiani et al reported a series of peripheral-type benzodiazepine receptor (PBR) ligands, [53] that exposed an autonomous effect on the death of developing cancer cells (Figure 11). Several of these benzoxazepine compounds, 85 and 86 were found to be the most potent ligands for this receptor.…”

1,5‐Benzoxazepines as a unique and potent scaffold for activity drugs: A review

“…[39] Overall, this study showed for the first time the PBOX-6-induced reactive oxygen species the molecular and cellular mechanisms in PBOX-6-induced cell death in neuroblastoma. [40] The same group of researchers designed and synthesized a series that drives colon tumorigenesis. [41] Moreover, CDK8 has been related to colorectal cancer and melanoma and restrains increased activation of the gene in acute myeloid leukemia cells.…”