Distinct effects of etoposide on glutamine-addicted neuroblastoma

Abstract

The majority of anticancer drugs are DNA-damaging agents, and whether or not they may directly target mitochondria remains unclear. In addition, tumors such as neuroblastoma exhibit addiction to glutamine in spite of it being a nonessential amino acid. Our aim was to evaluate the direct effect of widely used anticancer drugs on mitochondrial activity in combination with glutamine withdrawal, and possible apoptotic effects of such interaction. Our results revealed that etoposide inhibits mitochondrial respiratory chain Complex I causing the leakage of electrons and the superoxide radical formation. However, it was not sufficient to induce apoptosis, and apoptotic manifestation was detectable only alongside the withdrawal of glutamine, a precursor for antioxidant glutathione. Thus, the simultaneous depletion of glutathione and destabilization of mitochondria by ROS can compromise the barrier properties of the mitochondrial membrane, leading to cytochrome c release and the activation of the mitochondrial apoptotic pathway. Thus, the depletion of antioxidants or the inhibition of the pathways responsible for cellular antioxidant response can enhance mitochondrial targeting and strengthen antitumor therapy.

Aglycemic growth enhances carbohydrate metabolism and induces sensitivity to menadione in cultured tumor-derived cells

“…Though chemotherapeutic drugs often have multiple associated mechanisms of action, metabolic liabilities are commonly suggested to be important for their anti-cancer effects. For example, sorafenib, doxorubicin, and etoposide have all been shown to alter mitochondrial respiratory function in cancer cells [3][4][5]. Additionally, many new drugs (e.g., sorafenib derivatives), which are also likely to have metabolic implications, are being developed for use in late-stage HCC and other cancers [1,2,6,7].…”

Developing targeted therapies for neuroblastoma by dissecting the effects of metabolic reprogramming on tumor microenvironments and progression

“…Such underlined mechanisms might be highly ascribed to the glutamate metabolism and acetyl CoA addition, which were supported by the single-cell metabolic flux analysis (Figure 13 Q to S). Previous studies have shown that glutamate metabolism aided in clearance of ROS from mitochondria, preserved the integrity of mitochondrial membrane and prevented the pathways of mitochondrial-dependent apoptosis from activating, thereby conferring NB cells with resistance to etoposide [73]. Moreover, it has been reported that acetyl-CoA production was highly dependent on glutamate, and an excess of acetyl-CoA could counteract etoposide-induced apoptosis in tumors addicted to glutamate metabolism [74,75].…”

“…Our previous findings demonstrated that etoposide-induced mitochondrial damage, such as alterations in membrane potential, led to apoptosis of MPS-II NB cells through a mitochondria-dependent pathway (Figure 9). Besides, etoposide also inhibited mitochondrial respiratory chain complex I and induced ROS production [73]. However, MPS-I NB cells exhibited etoposide resistance (Figure 9), most likely due to their addiction to glutamate metabolism and acetyl-CoA.…”

“…However, MPS-I NB cells exhibited etoposide resistance (Figure 9), most likely due to their addiction to glutamate metabolism and acetyl-CoA. Reported studies have shown that highly active glutamate metabolism aided in the mitochondrial elimination of excess ROS, protected the mitochondrial membrane, and prevented the activation of mitochondria-dependent apoptotic pathways, thereby conferring etoposide resistance on NB cells with glutamate metabolism-addiction [73]. Glutamine deprivation could make NB cells re-sensitize to etoposide with recovery of apoptotic efficiency [73].…”

“…Reported studies have shown that highly active glutamate metabolism aided in the mitochondrial elimination of excess ROS, protected the mitochondrial membrane, and prevented the activation of mitochondria-dependent apoptotic pathways, thereby conferring etoposide resistance on NB cells with glutamate metabolism-addiction [73]. Glutamine deprivation could make NB cells re-sensitize to etoposide with recovery of apoptotic efficiency [73]. It has been reported that the generation of acetyl CoA is highly dependent on glutamate and directly occurs through reducing carboxylation [74].…”