Document Type

Article

Publication Date

2021

Publication Title

Cancers

Volume

13

Issue

20

Pages

5062 (1-26)

DOI

10.3390/cancers13205062

Abstract

In this study, we used B16-F10 cells grown in the dorsal skinfold chamber (DSC) preparation that allowed us to gain optical access to the processes triggered by photodynamic therapy (PDT). Partial irradiation of a photosensitized melanoma triggered cell death in non-irradiated tumor cells. Multiphoton intravital microscopy with genetically encoded fluorescence indicators revealed that bystander cell death was mediated by paracrine signaling due to adenosine triphosphate (ATP) release from connexin (Cx) hemichannels (HCs). Intercellular calcium (Ca2+) waves propagated from irradiated to bystander cells promoting intracellular Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria and rapid activation of apoptotic pathways. Combination treatment with S-nitrosoglutathione (GSNO), an endogenous nitric oxide (NO) donor that biases HCs towards the open state, greatly potentiated anti-tumor bystander killing via enhanced Ca2+ signaling, leading to a significant reduction of post-irradiation tumor mass. Our results demonstrate that HCs can be exploited to dramatically increase cytotoxic bystander effects and reveal a previously unappreciated role for HCs in tumor eradication promoted by PDT.

Comments

© 2021 by the authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Original Publication Citation

Nardin, C., Peres, C., Putti, S., ... Yang, G., Retamal, M. A., & Mammano, F. (2021). Connexin hemichannel activation by S-nitrosoglutathione synergizes strongly with photodynamic therapy potentiating anti-tumor bystander killing. Cancers 13(20), 1-26, Article 5062. https://doi.org/10.3390/cancers13205062

ORCID

0000-0002-0546-3173 (Mazzarda)

Share

COinS