Effects of cilengitide in osteoclast maturation and behavior

Chillà, Anastasia; Bianconi, Daniela; Geetha, Nisha; Dorda, Alexandra; Poettler, Marina; Unseld, Matthias; Sykoutri, Despoina; Redlich, Kurt; Zielinski, Christoph; Prager, Gerald W.

doi:10.1016/j.yexcr.2015.07.018

Cited by 9 publications

(11 citation statements)

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“…Triapine distinctly upregulated activating Src phosphorylation at Y416 specifically in the resistant subline. While, in accordance with the literature [67], Src phosphorylation was inhibited by cilengitide as single compound, combination with triapine synergistically enhanced this effect especially in SW480/tria cells to levels far above the control. Interestingly, the triapine-resistant cells exhibited a mild hypersensitivity to the Src inhibitor dasatinib.…”

Section: Discussionsupporting

confidence: 91%

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

et al. 2016

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Triapine, an anticancer thiosemicarbazone, is currently under clinical investigation. Whereas promising results were obtained in hematological diseases, trials in solid tumors widely failed. To understand mechanisms causing triapine insensitivity, we have analysed genomic alterations in a triapine-resistant SW480 subline (SW480/tria). Only one distinct genomic loss was observed specifically in SW480/tria cells affecting the phosphodiesterase 4D (PDE4D) gene locus. Accordingly, pharmacological inhibition of PDE4D resulted in significant triapine resistance in SW480 cells. Hence, we concluded that enhanced cyclic AMP levels might confer protection against triapine. Indeed, hyperactivation of both major downstream pathways, namely the protein kinase A (PKA)-cAMP response element-binding protein (Creb) and the exchange protein activated by cAMP (Epac)-Ras-related protein 1 (Rap1) signaling axes, was observed in SW480/tria cells. Unexpectedly, inhibition of PKA did not re-sensitize SW480/tria cells against triapine. In contrast, Epac activation resulted in distinct triapine resistance in SW480 cells. Conversely, knock-down of Epac expression and pharmacological inhibition of Rap1 re-sensitized SW480/tria cells against triapine. Rap1 is a well-known regulator of integrins. Accordingly, SW480/tria cells displayed enhanced plasma membrane expression of several integrin subunits, enhanced adhesion especially to RGD-containing matrix components, and bolstered activation/expression of the integrin downstream effectors Src and RhoA/Rac. Accordingly, integrin and Src inhibition resulted in potent triapine re-sensitization especially of SW480/tria cells. In summary, we describe for the first time integrin activation based on cAMP-Epac-Rap1 signaling as acquired drug resistance mechanism. combinations of triapine with inhibitors of several steps in this resistance cascade might be feasible strategies to overcome triapine insensitivity of solid tumors.

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Section: Discussionsupporting

confidence: 91%

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

et al. 2016

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“…The most prominent compound targeting integrins might be cilengitide, a cyclic RGD peptide that targets integrins αvβ3 and αvβ5 [214]. We and other groups could show in vitro and in vivo that this peptide inhibits attachment and invasion of different tumor cells [215,216,217,218,219,220,221]. However, cilengitide failed to provide benefit in a clinical trial phase III (CENTRIC study) [222].…”

Section: Hotspots For Anticancer Treatmentmentioning

confidence: 99%

Integrins in the Spotlight of Cancer

Bianconi

Unseld

Prager

2016

IJMS

Self Cite

127

110

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Integrins are heterodimeric cell surface receptors that bind to different extracellular ligands depending on their composition and regulate all processes which enable multicellular life. In cancer, integrins trigger and play key roles in all the features that were once described as the Hallmarks of Cancer. In this review, we will discuss the contribution of integrins to these hallmarks, including uncontrolled and limitless proliferation, invasion of tumor cells, promotion of tumor angiogenesis and evasion of apoptosis and resistance to growth suppressors, by highlighting the latest findings. Further on, given the paramount role of integrins in cancer, we will present novel strategies for integrin inhibition that are starting to emerge, promising a hopeful future regarding cancer treatment.

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“…Integrins can mediate the BC cells' adhesion to the extracellular matrix. Among the whole family, the ανβ3 integrin plays a vital role in regulating the migration of BC cells to the trabecular bone by binding to a tripeptide (Arg-Gly-Asp) present in vitro nectin, osteosialin, and osteopontin [31][32][33][34].…”

Section: Adhesionmentioning

confidence: 99%

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Shao

Varamini

2022

Cells

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Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients’ survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.

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Effects of cilengitide in osteoclast maturation and behavior

Cited by 9 publications

References 50 publications

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

Integrins in the Spotlight of Cancer

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

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