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.
Highlights
In the last decades, the correlation between oxidative stress (OS) and cancer onset has been highlighted by several pieces of evidence, but with contradictory findings
Dendrimer NPs have proved to be efficient in improving drugs therapeutic efficacy at lower dosages by behaving as “excipients” or enhancers of permeability, by altering the barrier properties of the intestinal epithelium, enhancing the permeation ability of the transported drug [61]
Following this current and successful trend, gallic acid (GA) was previously formulated in NPs, by its covalent Nbaonnodmattoeriaalsfi2f0th20,g1e0n, xerFaOtiRoPnE,EbRioRdEeVgIEraWdable dendrimer matrix (4) obtaining a peripherally GA-dec1o0raofte3d0 dendrimer (GAD), with appealing results from several points of view [54,55,56]
Summary
The correlation between oxidative stress (OS) and cancer onset has been highlighted by several pieces of evidence, but with contradictory findings. During the neoplastic transformation, there is an improvement in the production of reactive oxygen species (ROS), which supports tumor cell growth, by stimulating both redox-modulated signal transduction routes and transcription agents. In this regard, the use of ROS scavenging synthetic or natural compounds, counteracting the activation of redox sensitive pathways, could be employed as anti-carcinogenic for preventing the tumors onset and for treating the disease in the early stages. When chemotherapeutic drugs induce an increase in intracellular ROS levels, the intrinsic antioxidant defense decreases and cancer cell death occurs. Nanomaterials 2020, 10, x FOR PEER REVIEW pRnmsitRncipusnonyyreaOersOdotestunseeuoosrtaStSsrdcereteyobeeINCabomICNnmpntnbpernlebfocuiBurnlBcorntmeltadoatraeyorahirhiisrindgraongssdosieteie[oyndstfuodnsr1unaanoaftMmc–rrfrctgamitghiehMtoll3neltnlaiyyaYaygieeri]goacon,ct.nYt,atC(lapyneleneHguNrgu(HCraNrrrNdl[ddloodwrRoBiN1iwR,ol,oeggBegp–)yiansainpenst3)eriptpnhnepsnoeohna]bbairu.uetrteasseooeotocioortffciroetfottsi-oeagohuofochuneoomnebnbams-cnstlscltollitlsotoopsacttodaitipnuisnovwulsuowsvuoitcttmggetmdiuneuoo-uonc-ernradrmomgamnoadnitiindsrteeusnsrdeeoiakatkrnksntmtrtsir,ga,hihge-gf-aafamtaoaaootoaaounnbanuffrtrrbtrptmimddlmdtemomrsloelraecekirreoiphffihsotasittifairg,liatgo,rciteniigtogmicnsasficcmgsnhniahrttatdtacrisereip-sry-epoannaerdnraifnaoftanitdtigrttruisiesbutbeo.osnioukskgcslng,lymnT,mdeceey(ygwoa(e.hwiHHooncutncenTcchhfahtfoRneRhoehihaiteriunurcguiui))cmeeelvehdlrhdrfilgfdgeadncoaapoiirricrhlnmlritelrfnebebanrimcaimtcnsfieclsatrerpccrsd,ilsaeccslestvtuilrtiuraoesc,oni,snoeeefdtetldfrtfgisgilncelecefecouepeoloaa,aaoslulnslofeicmtepttiamrpnluninmutpmoaerooootbrstrbosrfennereenieeaipionMbnnndtndnatnooarolsaetsnteeftYnsinbfnsbipivtdvpofdsyCeoiyeMroeooeiroxoorofNbfmrumxuoiugaYutaltdgi1hregnhnsenisdCea5sslesltdpeotdaynf%yNaaacosrcsnssttasoioyatroybttosotopidgaprmramisxf1[xdoatneato4io5icipiabmpcfebocc]cfh%fealf.aslcbeddiaenedcdtitlhhrnsidhhiisoioiooksffsefeesehe[ffemffeeme4etstmeoaiiraii.scr]ncracons.ose.hsoecerdencntntHintHkrihrlheateleadcteeuileruineranaaarhavurvmrsmdntdsatooassioiiic/nnp/aetopnunaoueoidnggydnlgygsrrsrl ffoolllloowweedd bbyy ssuurrggiiccaall rreesseeccttiioonn,, mmyyeellooaabbllaattiioonn aanndd rreessccuuee ooff aauuttoollooggoouuss sstteemm cceellll,, rraaddiiootthheerraappyy,, aanndd iinntteennssiivvee iimmmmuunnootthheerraappyy [[55]]
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