Photodynamic therapy (PDT) is an effective treatment for solid tumors, which involves the administration of a photosensitizing agent and subsequent light exposure to generate reactive oxygen species, leading to cell death in the illuminated tissue. The field of cell death has expanded significantly in the last decade, with novel mechanisms and signaling pathways orchestrating multiple cell death pathways being continuously unveiled. While apoptosis is the most well-known and extensively studied regulated cell death mechanism, emerging studies have identified additional regulated cell death pathways such as necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis. Some of which have been observed in PDT studies. Furthermore, the immunogenicity of these cell death modalities is under extensive investigation as the field progresses [1].
Over the past few years, we have focused on developing new bacteriochlorins with strong absorption in the NIR, and high phototoxicity and immunostimulatory properties. One such compound, redaporfin (a halogenated sulfonamide bacteriochlorin), has recently completed Phase I/II clinical trials for head and neck cancer (NCT02070432). Another derivative of smaller derivative, LUZ51 (a halogenated sulfonamide bacteriochlorin), has also shown promising results. The mode of action of this family of compounds have been focus of some of our studies. Our results demonstrated that the lipophilicity of these bacteriochlorins favors their accumulation in the endoplasmic reticulum and Golgi compartments, significantly influencing the subsequent biochemical mechanisms of cell death. Photo-activation of these compounds triggers various signs that may indicate the involvement of apoptosis, paraptosis, pyroptosis as well as a non-canonical form of autophagy. These findings highlight the complexity of PDT-mediated cell death and the probable overlap of mechanisms within multiple cell death pathways [2],[3].
[1] Claire Donohoe et al., “Cell Death in Photodynamic Therapy: From Oxidative Stress to Anti-Tumor
Immunity,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1872, no. 2 (December 2019): 188308, https://doi.org/10.1016/j.bbcan.2019.07.003.
[2] Lígia C Gomes‐da‐Silva et al., “Photodynamic Therapy with Redaporfin Targets the Endoplasmic Reticulum and Golgi Apparatus,” The EMBO Journal 37, no. 13 (July 2, 2018), https://doi.org/10.15252/embj.201798354.
[3] Lígia C. Gomes-da-Silva et al., “Recruitment of LC3 to Damaged Golgi Apparatus,” Cell Death & Differentiation 26, no. 8 (August 22, 2019): 1467–84, https://doi.org/10.1038/s41418-018-0221-5.