Abstract
During radiotherapy procedures, radiation-induced bystander effect (RIBE) can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO) was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2), at a relatively low concentration (20 µM), effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB) and micronucleus (MN). In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2) of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2) with a low concentration of 30 µM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1), MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX-2). The results can help mitigate RIBE-induced hazards during radiotherapy procedures.
Highlights
Radiation-induced bystander effect (RIBE) creates potential genetic hazards for normal tissues surrounding the targeted regions during radiotherapy procedures, and has been considered to have a close relationship with radiation-induced secondary cancers beyond the irradiated areas after radiotherapy [1,2]
Considering that Gerashchenko’s study [23] proved 5% irradiated cells did not affect the measurement of proteins in the bbyystander cells, the fraction of irradiated cells in our experiment should bbee lleesssstthhaann55%%..WWhhenenEErircicHHalal’lsl’sgrgoruopupadaodpotpetdedthtehme mixeixdedcecllecllucslutesrtemr omdoedl teol taossaessssetshsethmeumtaugteangiecnitiyciotyf boyfsbtaynstdaenrdAeLr cAeLllsc,etlhlse,ythmeiyxemdixtheeditrhraediriarateddiaatned banysdtabnydsetarncdelelrs cinelalsriantiao roaft1io:5otfo1f:5ortmo ftohremcltuhsetecrluasntdertahnend sthepenarsaetpedartahtedbythsteabnydsetranAdLecreAllsLwceitlhls mwaitghnmetiacgsneeptaicrasteiponartawtiiocne tfworictehefofrutrhtheefrurmthuetragmeuntiacigteynaicniatylyasnisa[l5y]s.isT[h5e]y
Contradictory biological effects induced by RIBE from different research models indicated that the mechanisms underlying RIBE were complicated
Summary
Radiation-induced bystander effect (RIBE) creates potential genetic hazards for normal tissues surrounding the targeted regions during radiotherapy procedures, and has been considered to have a close relationship with radiation-induced secondary cancers beyond the irradiated areas after radiotherapy [1,2]. YT.oTcooncofinrfmirmwhwehtheethreRrIRBIEBsEigsinganl(asl)(sh)ahdadbebeenencocmomplpelteetleylytrtarnansdsduucecdedininththeecceelll-lc-clulussteterr mmooddeell,,wweecceennttrriiffuuggeedd oonnllyy tthhee iirrrraaddiiaatteedd cceellllss ttoo ffoorrmm aacceellllcclulusstteerrffoorr2244hhaatt1111◦°CC,,aannddththeenn resuspended and mixed the irradiated cells with the non-irradiated bystander cells. Under such conditions, the fraction of p53BP1 positive cells and the number of foci per cell in the bystander cell indicated that the RIBE signal(s) had been completely transduced during incubation of the mixed multicellular cluster and no more RIBE took place after the cell cluster was re-suspended. No distinct changes in the iNOS or COX-2 protein expression were observed in the irradiated cell population upon treatment with 30 μM CO (CORM-2) (Figure S3). Smigenanifi±caSnDc.eSsiignntihfiecadnifcfeesreinnctehsebdeitfwfeereennctehsebseatmwpeelenstahreesdaemteprlmesinaerde daentderdmififneerednacneds wdiiftfherpe
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