Photosensitizers in prostate cancer therapy

Abstract

The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies are being constantly developed to offer treatments similar to radical therapies, with limited side effects. Photodynamic therapy (PDT) is a promising strategy in delivering focal treatment in primary as well as post radiotherapy prostate cancer. PDT involves activation of a photosensitizer (PS) by appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). Several photosensitizers have been developed with a focus on treating prostate cancer like mTHPC, motexafin lutetium, padoporfin and so on. This article will review newly developed photosensitizers under clinical trials for the treatment of prostate cancer, along with the potential advantages and disadvantages in delivering focal therapy.

Keywords: photodynamic therapy; photosensitizers; prostate cancer.

Figure 1. Mechanism of PDT

Upon light activation, the photosensitizer is excited (S₀ to S₁). S₁ is converted to a more stable triplet state via intersystem crossing. Further, type I reactions involve the formation of ROS, whereas, the loss of energy in type II reactions leads to the formation of highly reactive singlet oxygen species; ultimately leading to cellular toxicity.

Figure 2. Mechanism of vascular targeted PDT

Vascular targeted PS accumulates in the tumor tissue. When light of suitable wavelength activates the PS, ROS is produced leading to vessel constriction, thrombosis and blood stasis; resulting in tumor necrosis.

Figure 3

Chemical structures of A. 5-ALA, B. verteporfin and C. pheophorbide a

Figure 4. 5-ALA-PDT induces cell death via apoptosis/necrosis

5-ALA accumulates in the mitochondria, and forms protoporphyrin IX using the heme synthesis pathway. Activation with light of specific wavelength causes a photodynamic reaction, producing ROS, which in turn leads to cell death.

Figure 5. Verteporfin inhibits the Hippo signaling pathway, blocking cell proliferation and survival

A. Under normal conditions, growth signals activate the Hippo signaling pathway, causing the activation of YAP/TAZ complex. This complex translocates into the nucleus to form YAP/TEAD which activates several growth factors, leading to cell growth and proliferation. B. Verteporfin blocks the translocation of YAP/TAZ into the nucleus, thus inhibiting cell growth and survival.

Figure 6. Structural difference between A. hematoporphyrin and B. Photofrin

Figure 7. Various cell death pathways modulated by PDT

The PS are taken up by the malignant cells and populate in various organelles like mitochondria and the endoplasmic reticulum. Light of suitable wavelength activates the PS which in turn causes release of cytochrome C from the mitochondria; leading to the activation of the caspase cascade. Pro-apoptotic factors like p53 are activated, thus inducing apoptosis. Formation of ROS may also lead to necrosis or autophagy. As shown earlier, the Hippo signaling pathway can be inhibited leading to inhibition in cell growth.