ABSTRACT Evidence accumulated over the past two decades has indicated that exposure of cell populations to ionizing radiation results in significant biological effects occurring in both the

irradiated and nonirradiated cells in the population. This phenomenon, termed the ‘bystander response’, has been shown to occur both _in vitro_ and _in vivo_ and has been postulated to

impact both the estimation of risks of exposure to low doses/low fluences of ionizing radiation and radiotherapy. Several mechanisms involving secreted soluble factors, oxidative metabolism

and gap-junction intercellular communication have been proposed to regulate the radiation-induced bystander effect. Our current knowledge of the biochemical and molecular events involved in

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS IONIZING RADIATION RESULTS IN A MIXTURE OF CELLULAR OUTCOMES INCLUDING MITOTIC

CATASTROPHE, SENESCENCE, METHUOSIS, AND IRON-DEPENDENT CELL DEATH Article Open access 23 November 2020 IONIZING RADIATION-INDUCED MITOPHAGY PROMOTES FERROPTOSIS BY INCREASING INTRACELLULAR

FREE FATTY ACIDS Article 12 October 2023 INHIBITION OF GPR68 INDUCES FERROPTOSIS AND RADIOSENSITIVITY IN DIVERSE CANCER CELL TYPES Article Open access 03 February 2025 ABBREVIATIONS * GJIC:

gap-junction intercellular communication * ROS: reactive oxygen species * SCE: sister-chromatid exchanges * CHO: Chinese hamster ovary * SOD: superoxide dismutase * DPI: diphenyliodonium *

DMSO: dimethyl sulfoxide REFERENCES * Adler V, Yin Z, Tew KD and Ronai Z . (1999). _Oncogene_, 18, 6104–6111. * Allen RG and Tresini M . (2000). _Free Radic. Biol. Med._, 28, 463–499. *

Azzam EI, De Toledo SM, Gooding T and Little JB . (1998). _Radiat. Res._, 150, 497–504. * Azzam EI, de Toledo SM and Little JB . (2001). _Proc. Natl. Acad. Sci. USA_, 98, 473–478. * Azzam

EI, de Toledo SM and Little JB . (2003). _Cancer Res._ (in press). * Azzam EI, De Toledo SM, Spitz DR and Little JB . (2002). _Cancer Res._, 62, 5436–5442. * Babior BM . (1999). _Blood_, 93,

1464–1476. * Barcellos-Hoff MH and Brooks AL . (2001). _Radiat. Res._, 156, 618–627. * Bedford JS and Mitchell JB . (1974). _Br. J. Radiol._, 47, 687–696. * Bevans CG, Kordel M, Rhee SK and

Harris AL . (1998). _J. Biol. Chem._, 273, 2808–2816. * Bishayee A, Hill HZ, Stein D, Rao DV and Howell RW . (2001). _Radiat. Res._, 155, 335–344. * Bishayee A, Rao DV and Howell RW .

(1999). _Radiat. Res._, 152, 88–97. * Blackburn RV, Spitz DR, Liu X, Galoforo SS, Sim JE, Ridnour LA, Chen JC, Davis BH, Corry PM and Lee YJ . (1999). _Free Radic. Biol. Med._, 26, 419–430.

* Bruzzone R, White TW and Goodenough DA . (1996). _BioEssays_, 18, 709–718. * Burdon RH . (1996). _Biochem. Soc. Trans._, 24, 1028–1032. * Burkitt MJ and Wardman P . (2001). _Biochem.

Biophys. Res. Commun._, 282, 329–333. * Chipman JK, Mally A and Edwards GO . (2003). _Toxicol. Sci._, 71, 146–153. * Chuaqui CA and Petkau A . (1987). _Radiat. Phys. Chem._, 30, 365–373. *

Clutton SM, Townsend KMS, Walker C, Ansell JD and Wright EG . (1996). _Carcinogenesis_, 17, 1633–1639. * D'Angio CT and Finkelstein JN . (2000). _Mol. Genet. Metab._, 71, 371–380. * De

Maio A, Vega VL and Contreras JE . (2002). _J. Cell. Physiol._, 191, 269–282. * Doble BW and Kardami E . (1995). _Mol. Cell. Biochem._, 143, 81–87. * Dowling-Warriner CV and Trosko JE .

(2000). _Neuroscience_, 95, 859–868. * Echetebu CO, Ali M, Izban MG, MacKay L and Garfield RE . (1999). _Mol. Hum. Reprod._, 5, 757–766. * Elfgang C, Eckert R, Lichtenberg-Frate H,

Butterweck A, Traub O, Klein RA, Hulser DF and Willecke K . (1995). _J. Cell Biol._, 129, 805–817. * Emerit I, Arutyunyan R, Oganesian N, Levy A, Cernjavsky L, Sarkisian T, Pogossian A and

Asrian K . (1995). _Free Radic. Biol. Med._, 18, 985–991. * Feinendegen LE . (2002). _Hum. Exp. Toxicol._, 21, 85–90. * Fernandez-Cobo M, Gingalewski C, Drujan D and De Maio A . (1999).

_Cytokine_, 11, 216–224. * Finkel T . (2000). _FEBS Lett._, 476, 52–54. * Finkel T and Holbrook NJ . (2000). _Nature_, 408, 239–247. * Gabbita SP, Robinson KA, Stewart CA, Floyd RA and

Hensley K . (2000). _Arch. Biochem. Biophys._, 376, 1–13. * Goldberg GS, Lampe PD and Nicholson BJ . (1999). _Nat. Cell Biol._, 1, 457–459. * Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A,

Witte L and Fuks Z . (1991). _Cancer Res._, 51, 2552–2558. * Halliwell B and Gutteridge JMC . (1989). _Free Radicals in Biology and Medicine_, 2nd edn. Clarendon Press: Oxford. Google

Scholar  * Herrlich P and Bohmer FD . (2000). _Biochem. Pharmacol._, 59, 35–41. * Hollowell Jr JG and Littlefield LG . (1968). _Proc. Soc. Exp. Biol. Med._, 129, 240–244. * Hosoi Y, Miyachi

H, Matsumoto Y, Enomoto A, Nakagawa K, Suzuki N and Ono T . (2001). _Int. J. Cancer_, 96, 270–276. * Huie RE and Padmaja S . (1993). _Free Radic. Res. Commun._, 18, 195–199. * Huo L,

Nagasawa H and Little JB . (2001). _Radiat. Res._, 156, 521–525. * Ignarro LJ, Fukuto JM, Griscavage JM, Rogers NE and Byrns RE . (1993). _Proc. Natl. Acad. Sci. USA_, 90, 8103–8107. * Iyer

R and Lehnert BE . (2000). _Cancer Res._, 60, 1290–1298. * John SA, Kondo R, Wang SY, Goldhaber JI and Weiss JN . (1999). _J. Biol. Chem._, 274, 236–240. * Kamata H and Hirata H . (1999).

_Cell Signal_, 11, 1–14. * Kasper M, Traub O, Reimann T, Bjermer L, Großmann H, Müller M and Wenzel KW . (1996). _Histochem. Cell Biol._, 106, 419–424. * Khan MA, Hill RP and Van Dyk J .

(1998). _Int. J. Radiat. Oncol. Biol. Phys._, 40, 467–476. * Kojima T, Mochizuki C, Mitaka T and Mochizuki Y . (1997). _Cell Struct. Funct._, 22, 347–356. * Kumar NM and Gilula NB . (1996).

_Cell_, 84, 381–388. * Lampe PD and Lau AF . (2000). _Arch. Biochem. Biophys._, 384, 205–215. * Lehnert BE and Goodwin EH . (1997). _Cancer Res._, 57, 2164–2171. * Liu K, Kasper M, Bierhaus

A, Langer S, Muller M and Trott KR . (1997). _Radiat. Res._, 147, 437–441. * Lo CW . (1996). _J. Bioenerg. Biomembr._, 28, 379–385. * Lopez-Barneo J, Lopez-Lopez JR, Urena J and Gonzalez C .

(1988). _Science_, 241, 580–582. * Lorimore SA, Coates PJ, Scobie GE, Milne G and Wright EG . (2001). _Oncogene_, 20, 7085–7095. * Lyng FM, Seymour CB and Mothersill C . (2000). _Br. J.

Cancer_, 83, 1223–1230. * Lyng FM, Seymour CB and Mothersill C . (2001). _Biochem. Soc. Trans._, 29, 350–353. * Matsumoto H, Hayashi S, Hatashita M, Ohnishi K, Shioura H, Ohtsubo T, Kitai R,

Ohnishi T and Kano E . (2001). _Radiat. Res._, 155, 387–396. * Meister A and Anderson ME . (1983). _Annu. Rev. Biochem._, 52, 711–760. * Meplan C, Richard MJ and Hainaut P . (2000).

_Biochem. Pharmacol._, 59, 25–33. * Morel F, Doussiere J and Vignais PV . (1991). _Eur. J. Biochem._, 201, 523–546. * Mothersill C, Stamato TD, Perez ML, Cummins R, Mooney R and Seymour C .

(2000). _Br. J. Cancer_, 82, 1740–1746. * Musil LS and Goodenough DA . (1991). _J. Cell Biol._, 115, 1357–1374. * Nagasawa H, Cremesti A, Kolesnick R, Fuks Z and Little JB . (2002). _Cancer

Res._, 62, 2531–2534. * Nagasawa H and Little JB . (1992). _Cancer Res._, 52, 6394–6396. * Narayanan PK, Goodwin EH and Lehnert BE . (1997). _Cancer Res._, 57, 3963–3971. * Narayanan PK,

LaRue KEA, Goodwin EH and Lehnert BE . (1999). _Radiat. Res._, 152, 57–63. * Ohba K, Omagari K, Nakamura T, Ikuno N, Saeki S, Matsuo I, Kinoshita H, Masuda J, Hazama H, Sakamoto I and Kohno

S . (1998). _Gut_, 43, 575–577. * Paulson AF, Lampe PD, Meyer RA, TenBroek E, Atkinson MM, Walseth TF and Johnson RG . (2000). _J. Cell Sci._, 113 (Part 17), 3037–3049. * Petkau A . (1978).

_Photochem. Photobiol._, 28, 765–774. * Pike LJ . (2003). _J. Lipid Res._, 44, 655–667. * Price BD and Calderwood SK . (1992). _Cancer Res._, 52, 3814–3817. * Prise KM, Belyakov OV, Folkard

M and Micheal BD . (1998). _Int. J. Radiat. Biol._, 74, 793–798. * Rubanyi GM, Ho EH, Cantor EH, Lumma WC and Botelho LH . (1991). _Biochem. Biophys. Res. Commun._, 181, 1392–1397. *

Schubert AL, Schubert W, Spray DC and Lisanti MP . (2002). _Biochemistry_, 41, 5754–5764. * Schulze-Osthoff K, Bauer M, Vogt M, Wesselborg S and Baeuerle PA . (1997). _Oxidative Stress and

Signal Transduction_. Forman HJ, Cadenas E (eds). Chapman & Hall: New York, pp. 239–259. Book  Google Scholar  * Shao C, Furusawa Y, Aoki M, Matsumoto H and Ando K . (2002). _Int. J.

Radiat. Biol._, 78, 837–844. * Sherman MP, Aeberhard EE, Wong VZ, Griscavage JM and Ignarro LJ . (1993). _Biochem. Biophys. Res. Commun._, 191, 1301–1308. * Simon AM and Goodenough DA .

(1998). _Trends Cell Biol._, 8, 477–483. * Spitz DR, Sim JE, Ridnour LA, Galoforo SS and Lee YJ . (2000). _Ann. NY Acad. Sci._, 899, 349–362. * Suchyna TM, Nitsche JM, Chilton M, Harris AL,

Veenstra RD and Nicholson BJ . (1999). _Biophys. J._, 77, 2968–2987. * Tonon R and D'Andrea P . (2002). _Biorheology_, 39, 153–160. * Trosko JE and Inoue T . (1997). _Stem Cells_, 15

(Suppl. 2), 59–67. * Uchida A, Mizutani Y, Nagamuta M and Ikenaga M . (1989). _Immunopharmacol. Immunotoxicol._, 11, 507–519. * Vance MM and Wiley LM . (1999). _Radiat. Res._, 152, 544–551.

* Veenstra RD . (1996). _J. Bioenerg. Biomembr._, 28, 327–337. * Weill D, Gay F, Tovey MG and Chouaib S . (1996). _J. Interferon Cytokine Res._, 16, 395–402. * Willecke K, Eiberger J, Degen

J, Eckardt D, Romualdi A, Guldenagel M, Deutsch U and Sohl G . (2002). _Biol. Chem._, 383, 725–737. * Wink DA, Hanbauer I, Grisham MB, Laval F, Nims RW, Laval J, Cook J, Pacelli R, Liebmann

J, Krishna M, Ford PC and Mitchell JB . (1996). _Curr. Top. Cell Regul._, 34, 159–187. * Wu LJ, Randers-Pehrson GR, Xu A, Waldren CA, Geard CR, Yu ZL and Hei TK . (1999). _Proc. Natl. Acad.

Sci. USA_, 96, 4959–4964. * Xie QW, Kashiwabara Y and Nathan C . (1994). _J. Biol. Chem._, 269, 4705–4708. * Zhou H, Randers-Pehrson G, Waldren CA, Vannais D, Hall EJ and Hei TK . (2000).

_Proc. Natl. Acad. Sci. USA_, 97, 2099–2104. * Zhou HN, Suzuki M, Randers-Pehrson R, Chen G, Trosko J, Vannais D, Waldren CA, Hall EJ and Hei TK . (2001). Download references

ACKNOWLEDGEMENTS We are deeply grateful to Drs Douglas Spitz, Roger Howell, Andrew Harris, Ashok Hospattankar, Perumal Venkatachalam and Veronica Leautaud for helpful comments and

discussions. Research Grants FG02-98ER62685 (JBL) and FG02-02ER63447 (EA) from the US Department of Energy, 1RO1-CA92262-01A1 from the National Institutes of Health and 02-1081-CCR-S0 from

the New Jersey Commission on Cancer Research (EA) supported this investigation. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Radiology, UMDNJ, New Jersey Medical School,

Newark, NJ, USA Edouard I Azzam & Sonia M de Toledo * Laboratory of Radiobiology, Harvard School of Public Health, Boston, MA, USA Edouard I Azzam & John B Little Authors * Edouard I

Azzam View author publications You can also search for this author inPubMed Google Scholar * Sonia M de Toledo View author publications You can also search for this author inPubMed Google

Scholar * John B Little View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Edouard I Azzam. RIGHTS AND PERMISSIONS

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * bystander response * ionizing radiation * _α_-particles

* gap-junction intercellular communication * oxidative stress