Photodynamic therapy combined with a cysteine proteinase inhibitor synergistically decrease VEGF production and promote tumour necrosis in a rat mammary carcinoma

Zsebik, Barbara; Symonowicz, Krzysztof; Saleh, Yousif; Ziółkowski, Piotr; Bronowicz, Andrzej; Vereb, György

doi:10.1111/j.1365-2184.2007.00420.x

Cited by 7 publications

(3 citation statements)

References 30 publications

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“…Our strategy is a true combination therapy that achieves stoichiometric inactivation of the CTSB target with release of a catalyst that generates 1 O 2 to induce cell death. Given that high levels of synergy have already been reported in combining PDT and cysteine cathepsin inhibition in vivo for the treatment of breast cancer, our conjugates or derivatives thereof are promising leads for the development of novel breast cancer therapeutics. Although our method will be more effective for early-stage and localized disease than for late-stage metastatic cancer, we propose it will extend PDT to breast cancer, a cancer type for which there are no clinically approved protocols in place. , In particular, new approaches for treating TNBC are needed because TNBC is especially hard to eradicate with follow-up chemotherapy including tamoxifen or trastuzumab that work for ER or HER2 positive types .…”

Section: Resultsmentioning

confidence: 99%

Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers

et al. 2018

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Dual action agents containing a cysteine protease inhibitor and Rubased photosensitizer for photodynamic therapy (PDT) were designed, synthesized, and validated in 2D culture and 3D functional imaging assays of triple-negative human breast cancer (TNBC). These combination agents deliver and release Rubased PDT agents to tumor cells and cause cancer cell death upon irradiation with visible light, while at the same time inactivating cathespin B (CTSB), a cysteine protease strongly associated with invasive and metastatic behavior. In total five Rubased complexes were synthesized with the formula [Ru(bpy)2(l)](O2CCF3)2 (3), where bpy = 2,2′-bipyridine and 1 = a bipyridine-based epoxysuccinyl inhibitor; [Ru(tpy)(NN)(2)](PF6)2, where tpy = terpiridine, 2 = a pyridine-based epoxysuccinyl inhibitor and NN = 2,2′-bipyridine (4); 6,6′-dimethyl-2,2′-bipyridine (5); benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine (6); and 3,6-dimethylbenzo[i]-dipyrido[3,2-a:2′,3′ -c]phenazine (7). Compound 3 contains a [Ru(bpy)3]2+ fluorophore and was designed to track the subcellular localization of the conjugates, whereas compounds 4–7 were designed to undergo either photoactivated ligand dissociation and/or singlet oxygen generation. Photochemical studies confirmed that complexes 5 and 7 undergo photoactivated ligand dissociation, whereas 6 and 7 generate singlet oxygen. Inhibitors 1–7 all potently and irreversibly inhibit CTSB. Compounds 4–7 were evaluated against MDA-MB-231 TNBC and MCF-10A breast epithelial cells in 2D and 3D culture for effects on proteolysis and cell viability under dark and light conditions. Collectively, these data reveal that 4–7 potently inhibit dye-quenched (DQ) collagen degradation, whereas only compound 7 causes efficient cell death under light conditions, consistent with its ability to release a Ru(II)-based photosensitizer and to also generate 1O2.

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Section: Resultsmentioning

confidence: 99%

Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers

et al. 2018

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“…Taking advantage of the properties of cysteine peptidase inhibitors originating from the human placenta or chicken egg white, not only is it possible to control cysteine peptidase activity but also to reduce the concentration of VEGF and its receptors. Furthermore, a very significant growth of necrosis of the neoplastic tumour, which also decreased, was observed [29,30].…”

Section: Discussionmentioning

confidence: 93%

Inhibition of cysteine peptidase activity in ascitic fluid in pancreatic cancer patients.

Agrawal

Kielan²,

Katib³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:The work's objective is to answer the question whether there is any possibility of activity inhibition of cysteine peptidases inhibitors playing an important role in key processes accompanying cancer formation, including pancreas. There is a justified speculation that specific inhibitors of these enzymes may inhibit development of cancer processes by inhibiting their activity. In vitro studies confirmed that these enzymes in ascitic fluid were inhibited with egg whites inhibitors even to 90% of their original activity.

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“…VEGF is a potent pro-angiogenic cytokine that is also known to promote proliferation and survival of endothelial cells (ECs) as well as vascular permeability ( 18 , 19 ). VEGF is expressed in vascularized tissues and is critical for normal and pathological angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

P18 peptide, a functional fragment of pigment epithelial-derived factor, inhibits angiogenesis in hepatocellular carcinoma via modulating VEGF/VEGFR2 signalling pathway

et al. 2017

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Abstract. The P18 peptide is a functional fragment of pigment epithelial-derived factor (PEDF), which is an endogenic angiogenesis inhibitor. This study sought to determine the anti-angiogenic bioactivity of the P18 peptide in hepatocellular carcinoma (HCC) and to elucidate the underlying mechanism. Xenograft tumour growth assays demonstrated the P18 peptide suppressed angiogenesis of HCC in vivo. Wound healing, Transwell and Matrigel-culture assays indicated that the P18 peptide inhibited the cell migration and tube formation of endothelial cells (ECs) in vitro. Cell viability and apoptosis assessed by Cell Counting Kit-8 (CCK-8) and flow cytometry assays suggested that the P18 peptide inhibited angiogenesis by inducing apoptosis of ECs. Angiogenesis-and signal transduction-associated molecules analysed by western blot demonstrated that the P18 peptide targets vascular endothelial cell growth factor receptor 2 (VEGFR2) on ECs. In conclusion, by inhibiting the phosphorylation of VEGFR2, the P18 peptide modulates signalling transduction between VEGF/VEGFR2 and suppresses activation of the PI3K/Akt cascades, leading to an increase in mitochondrial-mediated apoptosis and anti-angiogenic activity. This bioactivity of the P18 peptide may represent a novel therapeutic strategy for the treatment of HCC.

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Photodynamic therapy combined with a cysteine proteinase inhibitor synergistically decrease VEGF production and promote tumour necrosis in a rat mammary carcinoma

Abstract: The combination of PDT and CPI could be a useful approach in tumour therapy as the two agents appear to be synergistic and probably decrease VEGF production by the tumour tissue.

Cited by 7 publications

References 30 publications

Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers

Catch and Release Photosensitizers: Combining Dual-Action Ruthenium Complexes with Protease Inactivation for Targeting Invasive Cancers

Inhibition of cysteine peptidase activity in ascitic fluid in pancreatic cancer patients.

P18 peptide, a functional fragment of pigment epithelial-derived factor, inhibits angiogenesis in hepatocellular carcinoma via modulating VEGF/VEGFR2 signalling pathway

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