Neuroblastoma is a type of pediatric
cancer. The sensitivity of
neuroblastoma (NB)
cancer cells to
chemotherapy and radiation is inhibited by the presence of
antioxidants, such as
glutathione (GSH), which is crucial in counteracting the endogenous production of
reactive oxygen species (ROS). We have previously demonstrated that cells depleted of GSH undergo apoptosis via oxidative stress and
Protein kinase C (PKC) δ activation. In the present study, we transfected PKCδ in NB cells resistant to oxidative death induced by L-
buthionine-S,R-sulfoximine (BSO), a GSH-depleting agent. Cell responses, in terms of ROS production, apoptosis and DNA damage were evaluated. Moreover, PKCδ activation was monitored by analyzing the phosphorylation status of
threonine 505 residue, carrying out PKC activity assay and investigating the subcellular localization of the
kinase. The cell responses obtained in BSO-resistant cells were also compared with those obtained in BSO-sensitive cells subjected to the same experimental protocol. Our results demonstrate, for the first time, that PKCδ induces
DNA oxidation and ROS overproduction leading to apoptosis of BSO-resistant NB cells and potentiates the cytotoxic effects induced by BSO in sensitive cells. Moreover, PKCδ overexpression enhances the sensitivity of NB cells to
etoposide, a well-characterised drug, commonly used in
neuroblastoma therapy. Altogether our data provide evidence of a
pro-oxidant role of PKCδ that might be exploited to design new therapeutic strategies aimed at selective killing of
cancer cells and overcoming drug resistance. However, it becomes evident that a more detailed understanding of ROS-mediated signaling in
cancer cells is necessary for the development of redox-modulated therapeutic approaches.