Dendrimer Nanodevices and Gallic Acid as Novel Strategies to Fight Chemoresistance in Neuroblastoma Cells

Abstract

Human neuroblastoma (NB), a pediatric tumor inclined to relapse, after an initial response to therapy, usually develops resistance. Since several chemotherapeutics exert anticancer effect by increasing reactive oxygen species (ROS), NB cells overproduce antioxidant compounds becoming drugs-resistant. A strategy to sensitize NB cells to chemotherapy involves reducing their antioxidant defenses and inducing ROS overproduction. Concerning this, although affected by several issues that limit their clinical application, antioxidant/pro-oxidant polyphenols, such as gallic acid (GA), showed pro-oxidant anti-cancer effects and low toxicity for healthy cells, in several kind of tumors, not including NB. Herein, for the first time, free GA, two GA-dendrimers, and the dendrimer adopted as GA reservoir were tested on both sensitive and chemoresistant NB cells. The dendrimer device, administered at the dose previously found active versus sensitive NB cells, induced ROS-mediated death also in chemoresistant cells. Free GA proved a dose-dependent ROS-mediated cytotoxicity on both cell populations. Intriguingly, when administered in dendrimer formulations at a dose not cytotoxic for NB cells, GA nullified any pro-oxidant activity of dendrimer. Unfortunately, due to GA, nanoformulations were inactive on NB cells, but GA resized in nanoparticles showed considerable ability in counteracting, at low dose, ROS production and oxidative stress, herein induced by the dendrimer.

Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription

“…It was reported that gallic acid showed anti-cancer activity in some cancer cells that probably involved the production of ROS [ 25 , 26 ]. We measured the levels of intracellular ROS using 2′,7′-dichlorofluorescein (DCF) diacetate, a cell-permeable probe.…”

Development of a Fast, Low‐Cost, Conservative and Ecological Method for Quantifying Gallic Acid in Polymeric Formulations by FTIR Spectroscopy in Solution

“…GA attracts the interest of researchers mainly for its antioxidant capacity and ability in counteracting oxidative stress (OS) and correlated diseases as cancer, HIV, ulcer, inflammation, bacterial infections, fungi infections and neurodegenerative disorders …”

“…In the last decade, several natural or synthetic polymers, including acryloyldimethyl taurate with propylene glycol, polylactic‐co‐glycolic acid (PLGA), polyethylene glycol (PEG), chitosane, cyclodextrins, dextrane and dendrimers such as poly(amidoamine) (PAMAM) or polyester‐based ones have emerged as promising carrier systems for GA.…”

“…UV‐Vis spectroscopy, can be helpful for the detection of GA in polymer matrices . by using the colorimetric Folin‐Ciocalteu's (FC) or Folin‐Denis (FD) methods …”

“…In FTIR spectroscopy, GA presents specific regions of absorption, that may allow the rapid and unequivocal detection of GA. In this regard, very recently, FTIR has been successfully exploited for qualitative investigation of GA‐loaded dendrimer nanoparticles and for detection of GA presence into the dendrimer cavities, but it was not exploited for determining the GA concentration, that was assessed by UV‐Vis and FC method as usual, with the unhappy loss of sample.…”