Tumor cell survival pathways activated by photodynamic therapy: a molecular basis for pharmacological inhibition strategies

Abstract

Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.

RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death

“…Role of p38 MAPK in cell survival after PDT-induced cell death is currently controversial [51]. In our study, p38 is related to an MK2-dependent phosphorylation of TSC2 serine 1254 which is suggested to be a clear pro-survival axis to activate a salutary autophagy which occurs as soon as 15 min after irradiation [14].…”

Photosensitizers Imprinting Intracellular Signaling Pathways in Dermato-Oncology Therapy

“…For instance, such ER-related oxidative stress was reported for a PDT model with sodium-porfimer photosensitizer, which conducts to protein polyubiquitination, carbonylation and ER lumen enlargement [65]. As a result, the UPR constitutively activated in tumors, as many other protection mechanisms [83], will protect tumor cells against anticancer therapies such as PDT [74].…”

“…As PDT means an oxidative stress upon target cells, many studies related to signaling pathways were treated through the prism of oxidative stress and therefore extrapolated to PDT. Consequently, recent works refer to signaling pathways in PDT as to signaling pathways activated in cells subjected to oxidative stress [74].…”

Fullerenes in biology and medicine

“…ROS cause oxidative damage to nearly all types of biomolecules (proteins, lipids and nucleic acids) and tumor cell death. 67 PDT has remarkably improved selectivity and fewer side effects than traditional anticancer therapies. 68 …”