MALDI imaging detects endogenous digoxin in glioblastoma cells infected by Zika virus—Would it be the oncolytic key?

Abstract

Recently, microcephaly cases have increased in Americas and have been matter of concern due to Zika virus (ZIKV) recent outbreak. Previous studies have shown that ZIKV‐infected progenitor neuronal cells present morphological abnormalities and increased rates of cell death, which may be indicators of microcephaly causes. As recent studies indicate ZIKV' tropism for brain cells, how would a glioblastoma (GBM) lineage behave under ZIKV infection, considering GBM the most common and malignant brain tumor in adults, presenting extreme chemoresistance and high morbidity and mortality rates? The current trend of using genetically engineered oncolytic pathogens as a safe way to eliminate tumors is under development, with trials already in course. Therefore, the present study evaluated the possible oncolytic effects and metabolomic alterations of ZIKV infection at human malignant M059J GBM cells. Microscopic evaluation was performed by using optical microscopy, which showed cytopathic effects induced by ZIKV at GBM cells. For the metabolomics study, both control and infected cell cultures were submitted to matrix laser desorption/ionization mass spectrometry imaging analysis. Mass spectrometry data were submitted to partial least squares discriminant analysis statistical analysis, and distinct biomarkers were elected for each infected groups. This study brings light to unexpectedly induced metabolic changes, as endogenous digoxin as important biomarker for ZIKV‐GBM group, associated with cytopathic effects induced by viral infection. These result evidences that genetically engineered ZIKV might be a potential new strategy for neural cancer management through the induction of endogenous digoxin synthesis in GBM cells.

Metabolic alterations induced by attenuated Zika virus in glioblastoma cells

“…In line with the toxic effects of ZVp observed in the present research, previous studies have shown cell survival rate and cycle alterations due to ZIKV infection in glioblastoma cells, where tumor cells infected with ZIKV showed cytopathic effects [7] and apoptosis [6]. In addition to caspase-3 activation, shown by Zhu et al, some studies have also shown that apoptosis induced by ZIKV might be associated with perturbation of Toll-like receptors-3 (TLR3) network [15] and consequent inhibition of Sonic Hedgehog and RAS-ERK signaling [16].…”

“…According to the examples cited above, the focus of ZIKV scientific research has been upon its effects on neural progenitor/stem cells, mainly due to the evidences of viral neural tropism. However, new insights have emerged: ultimately, Zhu et al [6] and Lima et al [7] have considered ZIKV cell death associated with tropism for progenitor neural cells as a useful approach for neural tumor management. Their work showed that ZIKV is capable of infecting and effectively killing glioblastoma stem cells in comparison to normal neuronal cells, differently from other neurotropic viruses such as West Nile virus, which induces cell death in both normal and tumor neural cells.…”

“…Their work showed that ZIKV is capable of infecting and effectively killing glioblastoma stem cells in comparison to normal neuronal cells, differently from other neurotropic viruses such as West Nile virus, which induces cell death in both normal and tumor neural cells. Their findings suggest that genetically modified ZIKV would be a viable therapeutic strategy for glioblastomas control, as it is the most aggressive and chemoresistant neural tumor reported to date [6,7].…”

Inflammation markers in the saliva of infants born from Zika-infected mothers: exploring potential mechanisms of microcephaly during fetal development

“…Recent literature reports rely on the hypothesis that ZIKV promotes impaired NPCs growth, with associated apoptotic events, exerting similar effects over the systems of both newborns and adults 12 . The idea of interfering in the replication of cells with high metabolic rate has even elicited a whole new line of studies where ZIKV was used in an oncolytic-like strategy to treat aggressive gliomas, with results showing important cytopathic effects of the virus over the tumors 13,14 .…”

Alterações metabólicas em células de glioblastoma expostas a piriproxifeno

“…Estudos realizados por Lima et al (2017) [3] indicaram o Zika vírus como uma estratégia para tratar o glioblastoma, o tipo histológico de glioma mais agressivo. Além do efeito citopático, o vírus também demonstrou possuir ação na inibição da via de mTOR [4].…”