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

Abstract

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.

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 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.…”

“…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.…”

“…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].…”

Cell adhesion in cancer: Beyond the migration of single cells

“…This strategy resulted in one active compound (Fig. 3A) that inhibits the growth of drug-sensitive and -resistant cells in the micromolar range, reduces cell migration and invasive abilities, and presents an increased potency compared with sunitinib (107).…”

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

“…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 …”