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.
Highlights
Verteporfin causes photochemical damage to the mitochondria via reactive oxygen species (ROS) accumulation when activated by a 690 nm laser, it is routinely used as a PS for treating age-related macular degeneration (AMD) (Mellish and Brown, 2001)
Verteporfin causes photochemical damage to the mitochondria via ROS accumulation when activated by a 690 nm laser, it is routinely used as a PS for treating AMD (Mellish and Brown, 2001)
Studies showed that VP inhibits H. pyroli-induced proliferation, invasion, and metastasis of gastric cancer cells by disrupting the YAP1/TEAD4Connective Tissue Growth Factor (CTGF) axis and blocking transcription of epithelial mesenchymal transformation (EMT)-related genes (Kang et al, 2018; Li N. et al, 2018)
Summary
Verteporfin causes photochemical damage to the mitochondria via ROS accumulation when activated by a 690 nm laser, it is routinely used as a PS for treating AMD (Mellish and Brown, 2001). Studies showed that VP inhibits H. pyroli-induced proliferation, invasion, and metastasis of gastric cancer cells by disrupting the YAP1/TEAD4Connective Tissue Growth Factor (CTGF) axis and blocking transcription of EMT-related genes (Kang et al, 2018; Li N. et al, 2018). Targeted inhibition of YAP by VP inhibited the binding between YAP and the IL-6 promoter, and downregulated IL-6 and IL-11 in endometrial cancer cells, resulting in lower proliferation rates (Wang J. et al, 2019), increased sensitivity to adriamycin, and 45.36% decrease in tumor weight in the treated mice (Bang et al, 2019). VP inhibited HCQ and bafilomycin A1-induced autophagy in PC-3 and LNCaP prostate cancer cells, which increased p62 oligomerization and ROS production, and downregulated Nrf (antioxidant) and Bcl-xl (antiapoptotic) in prostate tumor cells and xenografts, while YAP1 overexpression had no effect on any of these factors (Wang et al, 2018). To summarize, repositioned VP can regulate the AKT/mTOR, IL-6/STAT3 and FAK signaling pathways, and inhibit CSCs partially independent of YAP
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