Verteporfin inhibits growth of human glioma in vitro without light activation

Al-Moujahed, Ahmad; Brodowska, Katarzyna; Stryjewski, Tomasz; Efstathiou, Nikolaos E.; Vasilikos, Ioannis; Cichy, Joanna; Miller, Joan W.; Gragoudas, Evangelos S.; Vavvas, Demetrios G.

doi:10.1038/s41598-017-07632-8

Cited by 72 publications

(65 citation statements)

References 52 publications

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“…Originally, verteporfin was defined as a clinical photosensitizer and is an inhibitor of the YAP‐TEAD interaction . In previous reports, verteporfin without light activation was reported to exhibit cytotoxicity while suppressing the YAP pathway at a concentration of approximately 2–20 μ m (10–100 times higher than the concentration used in the current study) . In the present study, siRNA‐mediated knockdown of YAP did not reduce the MMP in GSCs, whereas verteporfin led to a reduction in the YAP‐knocked down GSCs.…”

Section: Discussionsupporting

confidence: 38%

“…We therefore screened drugs in clinical use for their ability to reduce MMP as an indicator and identified verteporfin (VPF, trade name Visudyne ® ), a Food and Drug Administration‐approved photoactivating drug that is used clinically for macular degeneration, as a candidate drug for targeting the OXPHOS in GSCs . Indeed, it has been reported that VPF suppresses cell proliferation and induces cell death of various cancer cells including glioblastoma cells as its side effect so far, but there is no report in GSCs . The medical effect of verteporfin is photoactivation‐dependent .…”

Section: Resultsmentioning

confidence: 99%

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Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

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Section: Discussionsupporting

confidence: 38%

Section: Resultsmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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“…23 Binding of YAP TEAD can upregulate the expression of growth factors, including CTGF, Cyr61, Birc5 and Ki67, which in turn cause cell proliferation. 24 Our results indicate that SRPX2 overexpression inhibits the expression of CTGF, CYR61 and Birc5. SRPX2 overexpression suppressed CTGF, and the effects of Cyr61 and Birc5 expression were counteracted by YAP inhibition.…”

Section: Dovepressmentioning

confidence: 55%

<p>SRPX2 Promotes Cell Proliferation and Invasion in Osteosarcoma Through Regulating Hippo Signaling Pathway</p>

Wu¹,

Wang²,

Chen³

et al. 2020

OTT

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Background/Purpose: Osteosarcoma (OS), a primary bone malignancy, is characterized by a high rate of metastasis. It has been found that Sushi repeat containing protein X-linked 2 (SRPX2) is involved in tumor cell proliferation, adhesion, invasion and migration. The current work aimed to explore the effect of SRPX2 on OS cell invasion and proliferation. Methods: Immunohistochemistry (IHC), Western blotting and reverse transcriptionpolymerase chain reaction (RT-PCR) were used to detect the expression of the associated protein in OS tissues and cell lines. Cell counting kit-8 (CCK8), transwell and colony formation assays were used to determine cell viability, invasion, and proliferation, respectively. The in vivo tumorigenic ability of SRPX2 gene was determined using nude mouse tumorigenesis test. Results: SRPX2 knockdown suppressed the viability, while SRPX2 overexpression increased the invasion and colony formation ability of the cells in vitro. In vivo experiments demonstrated that SRPX2 knockdown inhibited tumor growth and invasion as evidenced by decreased Ki67 and N-cadherin levels, and increased E-cadherin level. Downregulation of SRPX2 increased YAP phosphorylation resulting in reduced nuclear translocation to activate Hippo signaling pathway. The promotion of cell viability, colony-forming ability, and invasion, and the inhibition of CTGF, Cyr61, and Birc5 levels promoted by SRPX2 overexpression were reversed by YAP inhibition. Conclusion: SRPX2 increased cell proliferation and invasion in osteosarcoma by activating Hippo signaling pathway.

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“…RNAs were increased in HBEC3s. Importantly, verteporfin is photo activated and inhibits YAP in the presence and absence of light (27,(41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Active epithelial Hippo signaling in idiopathic pulmonary fibrosis

Gokey

Sridharan

Xu³

et al. 2018

JCI Insight

114

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Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA (JUB). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF.

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Verteporfin inhibits growth of human glioma in vitro without light activation

Cited by 72 publications

References 52 publications

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

<p>SRPX2 Promotes Cell Proliferation and Invasion in Osteosarcoma Through Regulating Hippo Signaling Pathway</p>

Active epithelial Hippo signaling in idiopathic pulmonary fibrosis

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