Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma

Bianchini, Francesca; Portioli, Elisabetta; Ferlenghi, Francesca; Vacondio, Federica; Andreucci, Elena; Biagioni, Alessio; Ruzzolini, Jessica; Peppicelli, Silvia; Lulli, Matteo; Calorini, Lido; Battistini, Lucia; Zanardi, Franca; Sartori, Andrea

doi:10.1016/j.canlet.2018.12.021

Cited by 28 publications

(51 citation statements)

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“…Cyclic pentapeptides containing the RGD motif (cRGDfK) are used to improve the drug delivery and target selectivity of anti-cancer drugs [ 34 , 35 , 40 , 45 , 46 ]. Many studies have demonstrated the potential of RGD-containing peptides as vectors for delivering anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, cyclic peptides have been actively studied recently as biochemical tools and therapeutic agents because of their excellent stability, high resistance to exogenous peptidases, and high affinity and selectivity for binding to target biomolecules [44]. Cyclic pentapeptides containing the RGD motif (cRGDfK) are used to improve the drug delivery and target selectivity of anti-cancer drugs [34,35,40,45,46]. Many studies have demonstrated the potential of RGD-containing peptides as vectors for delivering anticancer agents.…”

Section: Plos Onementioning

confidence: 99%

“…These cyclic peptides have been used to ameliorate the cytotoxicity of drugs and reduce the side effects caused by toxicity without killing healthy cells. For instance, cyclic peptide conjugated antitumor small molecules, doxorubicin and paclitaxel, showed improved inhibition of growth and metastasis in cancer models [27,34,35].…”

Section: Introductionmentioning

confidence: 99%

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Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Park¹,

Kim

2020

PLoS ONE

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In human lung cancer progression, the EMT process is characterized by the transformation of cancer cells into invasive forms that migrate to other organs. Targeting to EMT-related molecules is emerging as a novel therapeutic approach for the prevention of lung cancer cell migration and invasion. Traf2-and Nck-interacting kinase (TNIK) has recently been considered as an anti-proliferative target molecule to regulate the Wnt signaling pathway in several types of cancer cells. In the present study, we evaluated the inhibitory effect of a tyrosine kinase inhibitor sunitinib and the integrin-α Ⅴ β 3 targeted cyclic peptide (cRGDfK) on EMT in human lung cancer cells. Sunitinib strongly inhibited the TGF-β1-activated EMT through suppression of Wnt signaling, Smad and non-Smad signaling pathways. In addition, the cRGDfK also inhibited the expression of TGFβ1-induced mesenchymal marker genes and proteins. The anti-EMT effect of sunitinib was enhanced when cRGDfK was treated together. When sunitinib was treated with cRGDfK, the mRNA and protein expression levels of mesenchymal markers were decreased compared to the treatment with sunitinib alone. Co-treatment of cRGDfK has shown the potential to improve the efficacy of anticancer agents in combination with therapeutic agents that may be toxic at high concentrations. These results provide new and improved therapies for treating and preventing EMT-related disorders, such as lung fibrosis and cancer metastasis, and relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

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Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Park¹,

Kim

2020

PLoS ONE

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“…During this endeavor, a new peptidomimetic chemotype of general formula c [Amp(Sub)RGD] was discovered (Figure ), in which a 4‐aminoproline residue (Amp) was used as a beneficial conformational restrain scaffold when embedded within a cyclic RGD peptide. Several compounds of type 4 showed excellent binding competence and good selectivity toward α V β 3 integrin in both cell‐free and in‐cell assays, which were exploited as intelligent vectors to selectively drive attached chemotherapeutics and/or imaging probes to tumor cells and tissues both in vitro and in vivo . With this experience, we were able to appreciate how even small structural variations within a series of closely related ligands could heavily impact the biological response in terms of cell internalization and in vivo antitumor activity …”

Section: Introductionmentioning

confidence: 99%

Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

Bugatti

Bruno

Sartori

et al. 2020

Chemistry A European J

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In recognition of the key role played by integrins in several life-threatening dysfunctions,t he search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimeticswith attracting a V b 3 integrin affinity and selectivity,t he designa nd straightforward synthesis of 18 new AmpRGD chemotypes bearinga dditional structuralv ariants were herein implemented, to shift toward peptide-like a V b 6 integrin targeted binders. The ligand competence of the synthesized products toward a V b 6 was evaluatedi nc ompetitive bindinga ssays on isolated receptors, and a V b 6 /a V b 3 selectivity was determined for as ubgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.

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“…These compounds proved chemically robust, competent, and selective binders of α V β 3 -overexpressing endothelial progenitor cells and melanoma cells, capable of (at least partially) entering these cells and inhibiting their proliferation. Furthermore, they demonstrated an ability to impair tumor-associated angiogenesis in vitro and in vivo, and to significantly decrease xenografted melanoma tumor growth in mice [18,19].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Sartori

Corno

Cesare

et al. 2019

Cancers

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Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αVβ3 covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αVβ3 at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.

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Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma

Cited by 28 publications

References 62 publications

Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

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Cell-targeted c(AmpRGD)-sunitinib molecular conjugates impair tumor growth of melanoma

Cited by 28 publications

References 62 publications

Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells

Shifting Towards αVβ6 Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

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Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline‐Based Cyclic Peptidomimetics