Cell death pathways in photodynamic therapy of cancer

Abstract

Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.

Keywords: apoptosis; autophagy; cancer; cell death; necrosis; photodynamic therapy.

Figure 1.

Schematic illustration of the mechanism of Photodynamic therapy (PDT). The photosensitizer (PS) is injected systemically and after sufficient time to allow its accumulation in the lesion light is delivered to produce reactive oxygen species (ROS). The tumor cells are killed by a mixture of necrosis and apoptosis, the blood supply is damaged and the host immune system activated.

Figure 2.

Jablonski diagram. Ground state PS absorbs a photon of correct wavelength to excite its electron to first excited singlet state that may (in addition to losing energy by heat or fluorescence emission) undergo intersystem crossing to long lived triplet state. This can undergo photochemistry by either electron transfer (Type I) or by energy transfer (Type II) to molecular oxygen to produce ROS.

Figure 3.

Photodynamic effect. An excited triplet state can either react directly with a reductant, e.g., an organic molecule in a cellular microenvironment, acquiring a hydrogen atom or electron to form a radical and produce a superoxide anion radical (O₂^•-), type I reaction or, more likely, transfer its energy to molecular oxygen (³O₂) and form singlet oxygen (¹O₂), type II reaction.

Figure 4.

Cell death pathways in PDT. The mode of cell death observed after PDT to some extent depends on the intracellular localization of the PS and PDT related damage to that organelle. PDT with PS localizing in mitochondria will lead to loss of membrane permeability and release of pro-apoptotic mediators while ER damage will release cellular deposits of calcium. PS that accumulates in lysosomes will release proteolytic enzymes upon illumination. Lysosomes may also fuse with autophagosomes to hydrolyse damaged organelles and recycle them during autophagy. In the excess of damage the cell will not survive despite initiation of autophagy. Necrosis as well as autophagy may be a dominant cell death mode after PDT when apoptosis is dysfunctional. It should be remembered that several PS may localize in more than one organelle and the activation of cell death pathways may occur concurrently (adapted from Oleinick et al. [132]).