Background
Verteporfin is a potent inhibitor of PD-L1 expression used for treatment in the age-related macular degeneration , port-wine stain birthmarks and cancer.[1]
In vitro experiment it shown that at 1μM versus 0.5 μM concentrations of verteporfin, it was sufficient to decrease PD-L1 expression in ATG5 depleted cells.[1] In vitro, at very low concentrations of verteporfin (0.1–0.2 μm) , verteporfin induced significant cell death in GSCs. However, 0.5 μm verteporfin had no effect on the cell death in differentiated GSCs, IMR90, rat NSCs or mouse astrocytes.[2] In vitro efficacy test it indicated treatment with 4, 8 and 12?μM verteporfin decreased significantly the expression levels of YAP, AXL and CYR61 mRNA in MCF-7, BT-474 and BT-549 cells. And verteporfin also downregulated the mRNA expression of CTGF in BT-474 and BT-549 cells.[3] Treatment with 0.5, 1, 2, and 5 μM verteporfin inhibited the viability of HeLa cells and had no obvious effect on H8 cells.[4]
In vivo study it demonstrated that treatment with 2 mg.kg-1 free verteporfin induced severe phototoxic adverse effects leading to the death of 5 out of 8 mice. However, mice were treated 8 mg.kg-1 nanostructured lipid carriers-verteporfin intravenously laser light exposure of tumors significantly inhibited tumor growth without visible toxicity.[5] In vivo, 2 mg/kg verteporfin infusion alone resulted in nitric oxide and malonyldialdehyde level increments in the retina.[6]
参考文献:
[1].Liang J, et al. Verteporfin Inhibits PD-L1 through Autophagy and the STAT1-IRF1-TRIM28 Signaling Axis, Exerting Antitumor Efficacy. Cancer Immunol Res. 2020 Jul;8(7):952-965. Kuramoto K, Yamamoto M, Suzuki S, Sanomachi T, Togashi K, Seino S, Kitanaka C, Okada M.
[2].Kuramoto K, et al. Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells. FEBS J. 2020 May;287(10):2023-2036.
[3].Wei C, Li X. Verteporfin inhibits cell proliferation and induces apoptosis in different subtypes of breast cancer cell lines without light activation. BMC Cancer. 2020 Oct 29;20(1):1042.
[4].Yin L, Chen G. Verteporfin Promotes the Apoptosis and Inhibits the Proliferation, Migration, and Invasion of Cervical Cancer Cells by Downregulating SULT2B1 Expression. Med Sci Monit. 2020 Oct 20;26:e926780.
[5].Michy T, et al. Verteporfin-Loaded Lipid Nanoparticles Improve Ovarian Cancer Photodynamic Therapy In Vitro and In Vivo. Cancers (Basel). 2019 Nov 8;11(11):1760.
[6].Turkuoglu P, et al. Retinal nitric oxide and malonyldialdehyde levels following photodynamic therapy. Indian J Ophthalmol. 2011 Jan-Feb;59(1):5-8.
维替泊芬是一种有效的 PD-L1 表达抑制剂，用于治疗年龄相关性黄斑变性、鲜红斑痣和癌症。[1]
体外实验表明，在 1μM 和 0.5μM 浓度的维替泊芬中，足以降低 ATG5 耗尽细胞中的 PD-L1 表达。[1] 在体外，在非常低的浓度下维替泊芬 (0.1-0.2 μm)，维替泊芬在 GSC 中诱导显着的细胞死亡。然而，0.5 μm维替泊芬对分化的GSCs、IMR90、大鼠NSCs或小鼠星形胶质细胞的细胞死亡没有影响。[2] 体外药效试验表明，4、8和12μM维替泊芬处理降低YAP、AXL和CYR61 mRNA在MCF-7、BT-474和BT-549细胞中的表达水平显着升高。维替泊芬也下调BT-474和BT-549细胞中CTGF mRNA的表达。[3]0.5、1、2和5 μM维替泊芬抑制HeLa细胞的活力并且没有对H8细胞有明显作用。[4]
体内研究表明，用 2 mg.kg-1 的游离维替泊芬治疗会引起严重的光毒性副作用，导致 8 只小鼠中有 5 只死亡。然而，小鼠接受 8 mg.kg-1 纳米结构脂质载体-维替泊芬静脉注射，激光照射肿瘤显着抑制肿瘤生长，且无可见毒性。[5] 在体内，单独输注 2 mg/kg 维替泊芬导致视网膜中的一氧化氮和丙二醛水平增加。[6]
Protocol
| Cell experiment [1]: |
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Cell lines
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RAW 264.7 cells
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Preparation Method
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RAW 264.7 cells were pretreated with 2 μM verteporfin for 2 h, then stimulated with LPS (1 μg/ml) for 22 h.
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Reaction Conditions
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2 μM; 2 h
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Applications
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When RAW 264.7 cells were treated with 2 μM verteporfin, GCSF, IL-6, CCL2, MCP-5, CCL5, and TNF-α were significantly inhibited compared with cells treated with LPS alone.
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| Animal experiment [2]: |
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Animal models
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C57BL/6 mice
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Preparation Method
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Lewis lung carcinoma cells (LLCs, 5 x 105 in 100 μl phosphate-buffered saline) were inoculated subcutaneously into C57BL/6 mice (male, 8–12 weeks) in both flanks. Five days after inoculation, mice were randomly divided into 4 groups and treated with vehicle, BMN 673 0.33 mg/Kg daily (oral gavage), verteporfin 30 mg/kg daily (intraperitoneal injection) and the combination of BMN 673 with verteporfin for 16 days. Tumors size were measured every 2 days by digital calipers to determine tumor volume using the formula [length/2] × [width2].
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Dosage form
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30 mg/kg; i.p.
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Applications
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Verteporfin treatment led to marked decreases in PD-L1 expression and increases in CD8 T cells especially in the combinatorial group of vereporfin and BMN 673.
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参考文献:
[1]. Wang Y, Wang L, Wise JTF, Shi X, Chen Z. Verteporfin inhibits lipopolysaccharide-induced inflammation by multiple functions in RAW 264.7 cells. Toxicol Appl Pharmacol. 2020 Jan 15;387:114852.
[2]. Liang J, et al. Verteporfin Inhibits PD-L1 through Autophagy and the STAT1-IRF1-TRIM28 Signaling Axis, Exerting Antitumor Efficacy. Cancer Immunol Res. 2020 Jul;8(7):952-965.
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