Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

Qiu, Beiying; Tan, Alison; Veluchamy, Amutha Barathi; Li, Yong; Murray, Hannah; Wei, Cheng; Liu, Chenghao; Busoy, Joanna Marie; Chen, Qi-Yin; Sistla, Srivani; Hunziker, Walter; Cheung, Chui Ming Gemmy; Wong, Tien Yin; Hong, Wanjin; Luesch, Hendrik; Wang, Xiaomeng

doi:10.1167/iovs.19-26936

Cited by 13 publications

(14 citation statements)

References 38 publications

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“…We have recently shown that apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing several angiogenic pathways ( Qiu et al., 2019 ). It was shown to act on retinal endothelial cells as well as pericytes and has the potential to overcome drug resistance to anti-VEGF therapy through its unique mechanism of action ( Qiu et al., 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the preclinical candidate apratoxin S10 exerted activity against cancer cells derived from highly vascularized tumors with 2000–5000 times greater potency than standard RTK inhibitors and also displayed antiangiogenic activity, in addition to its inherent anticancer properties ( Cai et al., 2017 ). Due to the unique mechanism, inhibiting VEGF secretion and downregulating other proangiogenic factors and receptors, apratoxin S4 was recently “repurposed” and shown to be highly effective in inhibiting ocular angiogenesis, and specifically pathological neovascularization, in organoids, rabbit and mouse models, and acting on retinal endothelial cells as well as pericytes ( Qiu et al., 2019 ). These data suggest that apratoxin S4 is also a treatment option to prevent blindness, even for populations that are resistant to anti-VEGF (standard-of-care) therapy.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

Cai

Ratnayake

Wang

et al. 2021

Current Research in Pharmacology and Drug Discovery

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Receptor tyrosine kinases (RTKs) have become major targets for anticancer therapy. However, resistance and signaling pathway redundancy has been problematic. The marine-derived apratoxins act complementary to direct kinase inhibitors by downregulating the levels of multiple of these receptors and additionally prevent the secretion of growth factors that act on these receptors by targeting Sec61α, therefore interfering with cotranslational translocation. We have profiled the synthetic, natural product-inspired apratoxin S4 against panels of cancer cells characterized by differential sensitivity to RTK inhibitors due to receptor mutations, oncogenic KRAS mutations, or activation of compensatory pathways. Apratoxin S4 was active at low-nanomolar to sub-nanomolar concentrations against panels of lung, head and neck, bladder, and pancreatic cancer cells, concomitant with the downregulation of levels of several RTKs, including EGFR, MET and others. However, the requisite concentration to inhibit certain receptors varied, suggesting some differential substrate selectivity in cellular settings. This selectivity was most pronounced in breast cancer cells, where apratoxin S4 selectively targeted HER3 over HER2 and showed greater activity against ER+ and triple negative breast cancer cells than HER2+ cancer cells. Depending on the breast cancer subtype, apratoxin S4 differentially downregulated transmembrane protein CDCP1, which is linked to metastasis and invasion in breast cancer and modulates EGFR activity. We followed the fate of CDCP1 through proteomics and found that nonglycosylated CDCP1 associates with chaperone HSP70 and HUWE1 that functions as an E3 ubiquitin ligase and presumably targets CDCP1, as well as potentially other substrates inhibited by apratoxins, for proteasomal degradation. By preventing cotranslational translocation of VEGF and other proangiogenic factors as well as VEGFR2 and other receptors, apratoxins also possess antiangiogenic activity, which was validated in endothelial cells where downregulation of VEGFR2 was observed, extending the therapeutic scope to angiogenic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

Cai

Ratnayake

Wang

et al. 2021

Current Research in Pharmacology and Drug Discovery

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“…For example, Decapterus tabl ingredients could significantly inhibit retinal neovascular tufts by inhibiting HIF expression in the oxygen-induced retinopathy (OIR) mouse model [ 39 ]. Apratoxin S4, derived from a marine cyanobacterial compound, exhibits potent anti-angiogenic effects in OIR mouse models, a mouse model of laser-induced choroidal neovascularization, and persistent retinal neovascularization rabbit model through mediating multiple angiogenic pathways [ 19 ]. Largazole was identified as one of the marine cyanobacteria metabolites with a novel chemical structure from a cyanobacterium of the genus Symploca and later reclassified as Caldora penicillata [ 20 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…So far, more than 25,700 compounds with unique chemical structures have been extracted from marine organisms, like molluscs, soft corals, fishes, and many microorganisms [ 18 ]. We recently described a marine natural product inspired inhibitor of cotranslational translocation, Apratoxin S4, as a potent anti-angiogenic compound in vitro and ex vivo and as an inhibitor of pathological ocular neovascularization in vivo [ 19 ]. The cyclodepsipeptide Largazole, isolated from a marine cyanobacterium, has been shown to have potent anti-proliferative properties in multiple cancer cell lines by inhibiting class I histone deacetylases (HDACs) [ 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Largazole Inhibits Ocular Angiogenesis by Modulating the Expression of VEGFR2 and p21

Qiu

Tan

et al. 2021

Marine Drugs

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Ocular angiogenic diseases, characterized by abnormal blood vessel formation in the eye, are the leading cause of blindness. Although Anti-VEGF therapy is the first-line treatment in the market, a substantial number of patients are refractory to it or may develop resistance over time. As uncontrolled proliferation of vascular endothelial cells is one of the characteristic features of pathological neovascularization, we aimed to investigate the role of the class I histone deacetylase (HDAC) inhibitor Largazole, a cyclodepsipeptide from a marine cyanobacterium, in ocular angiogenesis. Our study showed that Largazole strongly inhibits retinal vascular endothelial cell viability, proliferation, and the ability to form tube-like structures. Largazole strongly inhibits the vessel outgrowth from choroidal explants in choroid sprouting assay while it does not affect the quiescent choroidal vasculature. Largazole also inhibits vessel outgrowth from metatarsal bones in metatarsal sprouting assay without affecting pericytes coverage. We further demonstrated a cooperative effect between Largazole and an approved anti-VEGF drug, Alflibercept. Mechanistically, Largazole strongly inhibits the expression of VEGFR2 and leads to an increased expression of cell cycle inhibitor, p21. Taken together, our study provides compelling evidence on the anti-angiogenic role of Largazole that exerts its function through mediating different signaling pathways.

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“…Ap ra t ox i n E ( 55 ) Further studies on apratoxin S4 (50), revealed the molecule to possess potent antiangiogenic activity by inhibiting the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways [125]. This finding could path the way for the development of apratoxin S4 as a potential cure for prevention or treatment of vision loss.…”

Section: Apratoxin Amentioning

confidence: 99%

Marine Cyanobacteria: A Source of Lead Compounds and their Clinically-Relevant Molecular Targets

Tan

Phyo

2020

Molecules

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The prokaryotic filamentous marine cyanobacteria are photosynthetic microbes that are found in diverse marine habitats, ranging from epiphytic to endolithic communities. Their successful colonization in nature is largely attributed to genetic diversity as well as the production of ecologically important natural products. These cyanobacterial natural products are also a source of potential drug leads for the development of therapeutic agents used in the treatment of diseases, such as cancer, parasitic infections and inflammation. Major sources of these biomedically important natural compounds are found predominately from marine cyanobacterial orders Oscillatoriales, Nostocales, Chroococcales and Synechococcales. Moreover, technological advances in genomic and metabolomics approaches, such as mass spectrometry and NMR spectroscopy, revealed that marine cyanobacteria are a treasure trove of structurally unique natural products. The high potency of a number of natural products are due to their specific interference with validated drug targets, such as proteasomes, proteases, histone deacetylases, microtubules, actin filaments and membrane receptors/channels. In this review, the chemistry and biology of selected potent cyanobacterial compounds as well as their synthetic analogues are presented based on their molecular targets. These molecules are discussed to reflect current research trends in drug discovery from marine cyanobacterial natural products.

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Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

Abstract: Citation: Qiu B, Tan A, Veluchamy AB, et al. Apratoxin S4 inspired by a marine natural product, a new treatment option for ocular angiogenic diseases. Invest Ophthalmol Vis Sci.

Cited by 13 publications

References 38 publications

Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

Inhibition of cotranslational translocation by apratoxin S4: Effects on oncogenic receptor tyrosine kinases and the fate of transmembrane proteins produced in the cytoplasm

Largazole Inhibits Ocular Angiogenesis by Modulating the Expression of VEGFR2 and p21

Marine Cyanobacteria: A Source of Lead Compounds and their Clinically-Relevant Molecular Targets

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