Inhibiting autophagy increases the efficacy of low-dose photodynamic therapy
Received 28 May 2021, Revised 8 November 2021, Accepted 9 November 2021, Available online 12 November 2021.
https://www.sciencedirect.com/science/article/pii/S0006295221004536 (DOI)
Rupture and permeabilization of endocytic vesicles can be triggered by various causes, such as pathogenic invasions, amyloid proteins, and silica crystals leading to cell death and degeneration. A cellular quality control process, called lysophagy was recently described to target damaged lysosomes for autophagic sequestration within isolation membranes in order to protect the cell from the consequences of lysosomal leakage. This protective process, however, might interfere with treatment conditions, such as photodynamic therapy (PDT) and the intracellular drug delivery method photochemical internalization (PCI). PCI-induced permeabilization of endosomes and lysosomes is purposely triggered to release drugs that are sequestered in these organelles into the cytosol in order to synergistically kill cancer cells. Here, we show that photochemical treatment with the PCI-photosensitizer TPCS2a/fimaporfin results in both induction of autophagy and inhibition of the autophagic flux.
An active autophagic response and the presence of p62, however, is important for cancer cells to survive low-dose TPCS2a-PDT. Thus, targeting both p62 and autophagy together and independently, in a light-controlled/PCI based delivery of cancer therapeutics could increase the effectiveness of the treatment regime.
In conclusion, both autophagy and p62 independently and together are important for MA-11 cells to survive low-dose photochemical treatment using the clinically relevant PS TPCS2a/fimaporfin. Our study suggests that TPCS2a could be used in light-controlled/PCI-based delivery of RNAi cancer therapeutics for specific and efficient targeting of p62 and autophagy.
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