生物活性

• 描述Yes Associated Protein (YAP) is a downstream nuclear effector of the Hippo signaling pathway which plays a critical role in cell proliferation, apoptosis and angiogenesis as well as a potential target for cancer treatment. Verteporfin, a member of the porphyrin family, is clinically used in the treatment of neovascular macular degeneration with IC50 value of 1.0μM~10μM, varying in different cell types. Verteporfin is always used in photodynamic therapy as photosensitizer and in the Hippo-YAP pathway as inhibitor. As reported, verteporfin could suppress the proliferation of human PDAC PANC-1 and SW1990 cells, and induce apoptosis in dose- and time-dependent manners. Treatment with verteporfin inhibited the tumor growth on the PDAC xenograft model as well as downregulated cyclinD1 and cyclinE1, modulate of Bcl-2 family proteins and activate PARP. In addition, Verteporfn exhibited distinct inhibitory effect on the proliferation of four lines of Uveal melanoma cells (e.g., 92.1, Mel 270, Omm 1 and Omm 2.3), and induced apoptosis through the intrinsic pathway. According to a Phase I/II study of verteporfin photodynamic therapy, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm(3) at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy.
• 作用机制Verteporfin is transported in the plasma primarily by lipoproteins and once been activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin can locally damage neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. As singlet oxygen and reactive oxygen radicals are cytotoxic, Verteporfin can also be used to destroy tumor cells. https://www.drugbank.ca/drugs/DB00460
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  ARPE-19	~0.1 μg/ml	cytotoxicity assay	-	shows a dose-dependent toxicity	16987905
  ARPE-19	0.01 μg/ml	Function assay	-	increases VEGF and reduces PEDF expression	16987905
  ARPE-19	0.5 µg/ml	cytotoxicity assay	-	decreases viability by 55.5%	23441114

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• 动物研究
  剂量	Mice: 2 mg/kg - 6 mg/kg[1] (i.p.), 10 mg/kg[2] (i.p.), 100 mg/kg[3] (i.p.) Rat: 0.25 mg/kg - 1 mg/kg[4] (i.v.) Cynomolgus monkey: 0.25 mg/kg - 1 mg/kg[5] (i.v.)
  给药途径	i.p., i.v.
  动物药代数据	Animal Rats[6] Dose 2 mg/kg Administration i.v. AUC0-inf 13.653 μg·h/ml (male) 12.628 μg·h/ml (female) T1/2 7.12 h (male) 2.94 h (female) Tmax 0.017 h (male) 0.017 h (female) CL 2.44 ml/min/kg (male) 2.64 ml/min/kg (female) Cmax 20.360 μg/ml (male) 25.203 μg/ml (female) Vss 0.57 L/kg (male) 0.35 L/kg (female) AUC0→t 9.297 μg·h/ml (male) 11.323 μg·h/ml (female)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00211484	Age-Related Macular Degenerati... more >>ons. Subfoveal Neovascularization. Collapse <<	Phase 2	Completed	-	United States, New York ... more >> Manhattan Eye, Ear & Throat Hospital New York, New York, United States, 10021 Collapse <<
  NCT02587767	Acute Central Serous Chorioret... more >>inopathy Collapse <<	Not Applicable	Active, not recruiting	December 2018	China, Guangdong ... more >> Zhongshan Ophthalmic Center, Sun Yat-sen University Guangzhou, Guangdong, China, 510060 Collapse <<
  NCT02072408	Polypoidal Choroidal Vasculopa... more >>thy Without Active Polyp Collapse <<	Phase 4	Completed	-	Korea, Republic of ... more >> Seoul National University Bundang Hospital Seongnam, Gyunggi-do, Korea, Republic of Konyang University Kim's Eye Hospital Seoul, Korea, Republic of Samsung Medical Center Seoul, Korea, Republic of Collapse <<

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• 参考文献

• [1] Lui JW, Xiao S, et al. The Efficiency of Verteporfin as a Therapeutic Option in Pre-Clinical Models of Melanoma. J Cancer. 2019 Jan 1;10(1):1-10.

  [2] Zhou Y, Wang Y, et al. YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway. Cancer Cell Int. 2019 Jul 12;19:179.

  [3] Gavini J, Dommann N, et al. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019 Oct 3;10(10):749.

  [4] Chen B, Pogue BW, et al. Combining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy. Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1216-26.

  [5] Kramer M, Miller JW, et al. Liposomal benzoporphyrin derivative verteporfin photodynamic therapy. Selective treatment of choroidal neovascularization in monkeys. Ophthalmology. 1996 Mar;103(3):427-38.

  [6] Pharmacology/Toxicology Review

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