Chiara Nardin,1 Chiara Peres,1 Sabrina Putti,1 Tiziana Orsini,1 Claudia Colussi,2,3 Flavia Mazzarda,1,4 Marcello Raspa,1 Ferdinando Scavizzi,1 Anna Maria Salvatore,1 Francesco Chiani,1 Abraham Tettey-Matey,1 Yuanyuan Kuang,5 Guang Yang,5 Mauricio A. Retamal,6 and Fabio Mammano1,7,*


"1Institute of Biochemistry and Cell Biology (IBBC)-CNR, 00015 Rome, Italy; [email protected] (C.N.); [email protected] (C.P.); [email protected] (S.P.); [email protected] (T.O.); [email protected] (F.M.); [email protected] (M.R.); [email protected] (F.S.); [email protected] (A.M.S.); [email protected] (F.C.); [email protected] (A.T.-M.)
2Institute for Systems Analysis and Computer Science “A. Ruberti” (IASI)-CNR, 00168 Rome, Italy; [email protected]
3Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, 00168 Rome, Italy
4Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA
5Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; [email protected] (Y.K.); [email protected] (G.Y.)
6Universidad del Desarrollo, Centro de Fisiología Celular e Integrativa, Facultad de Medicina Clínica Alemana, Santiago 7780272, Chile; [email protected]
7Department of Physics and Astronomy “G. Galilei”, University of Padova, 35131 Padova, Italy
*Correspondence: [email protected]"


Cell Biology, Medical Research


"Bystander effects depend on direct cell-cell communication and/or paracrine signaling mediated by the release of soluble factors into the extracellular environment and may greatly influence therapy outcome. Although the limited data available suggest a role for intercellular gap junction channels, far less is known about the role of connexin hemichannels. Here, we investigated bystander effects induced by photodynamic therapy in syngeneic murine melanoma models in vivo. We determined that (i) photoactivation of a photosensitizer triggered calcium-dependent cell death pathways in both irradiated and bystander tumor cells; (ii) hemichannel activity and adenosine triphosphate release were key factors for the induction of bystander cell death; and (iii) bystander cell killing and antitumor response elicited by photodynamic therapy were greatly enhanced by combination treatment with S-nitrosoglutathione, which promoted hemichannel opening in these experimental conditions. Therefore, these findings in a preclinical model have important translational potential.



Excitation light was provided by a fluorescence lamp (pE-4000, CoolLED Ltd., Andover, NY, USA) equipped with excitation filters suitable for calcein-AM (Cat. No. FF01-474/27-25, Semrock) and mCherry (Cat. No. FF01-565/24-25, Semrock), respectively.

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The pE-4000 Universal Illumination System offers 16 selectable wavelengths from 365 - 770 nm, making it a highly flexible illuminator covering a wide variety of fluorophores

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