The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

Abstract

Verteporfin (VP) has long been clinically used to treat age-related macular degeneration (AMD) through photodynamic therapy (PDT). Recent studies have reported a significant anti-tumor effect of VP as well. Yes-associated protein (YAP) is a pro-tumorigenic factor that is aberrantly expressed in various cancers and is a central effector of the Hippo signaling pathway that regulates organ size and tumorigenesis. VP can inhibit YAP without photoactivation, along with suppressing autophagy, and downregulating germinal center kinase-like kinase (GLK) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). In addition, VP can induce mitochondrial damage and increase the production of reactive oxygen species (ROS) upon photoactivation, and is an effective photosensitizer (PS) in anti-tumor PDT. We have reviewed the direct and adjuvant therapeutic action of VP as a PS, and its YAP/TEA domain (TEAD)-dependent and independent pharmacological effects in the absence of light activation against cancer cells and solid tumors. Based on the present evidence, VP may be repositioned as a promising anti-cancer chemotherapeutic and adjuvant drug.

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

“…YAP not only activates ERK and AXL signaling, but also induces epithelial–mesenchymal transition (EMT) against EGFR-TKI treatment [ 16 ]. Several studies have shown that YAP inhibition can overcome resistance to chemotherapy [ 39 , 40 , 41 , 42 ]. For example, the combined treatment of EGFR-TKI with YAP inhibitors suppresses EGFR-TKI resistance [ 16 ].…”

Hot Spot Analysis of YAP-TEAD Protein-Protein Interaction Using the Fragment Molecular Orbital Method and Its Application for Inhibitor Discovery

“…Verteporfin (VP) was identified as the first small molecule inhibitor of YAP that modulates the YAP-dependent transcriptional activity of TEAD [20]. However, verteporfin may not be a very promising inhibitor of YAP-TEAD owing to its poor stability and solubility, and Hippo-independent effects [21][22][23]. Some peptide-mimicking drugs, including a cyclic peptide derived from the YAP (84-100) sequence [13], a hybrid peptide from YAP74-99 and VGLL4 protein sequence [24] and, more recently, a cysteine-rich peptide TB1G2 mimicking the α-helix binding domain of YAP, have been shown to directly disrupt YAP-TEAD interactions [25].…”

Targeting GRP78 enhances the sensitivity of HOS osteosarcoma cells to pyropheophorbide-α methyl ester-mediated photodynamic therapy via the Wnt/β-catenin signaling pathway

“…ROS levels is one of the main mechanisms that kill tumor cells [ 44 , 45 ], and the same phenomenon has been found in PDT [ 46 , 47 ]. After silencing the expression of GRP78, we also detected the ROS levels.…”