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

Abstract

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.

Cyclic RGD Pentapeptide Cilengitide Enhances Efficacy of Gefitinib on TGF-β1-Induced Epithelial-to-Mesenchymal Transition and Invasion in Human Non-Small Cell Lung Cancer Cells

“…Because of the high binding affinity and selectivity for integrin α δ β 3 and α δ β 5 in cancer cells, the use of cyclic peptides, such as cRGDfK and cRGDyK, has been one method for delivering therapeutic drugs in cancers (Chen and Chen, 2011;Kulhari et al, 2016). In a previous study, we confirmed that the cyclic pentapeptide containing the RGD motif (cRGDfK) enhances the inhibitory effect of TKI sunitinib on the TGF-β1-induced EMT (Park and Kim, 2020). The cRGDfK not only promotes the NSCLC cell death-inducing effect of gefitinib, but also increases the inhibitory effect on mesenchymal marker mRNA and protein expression.…”

Synthesis and Biological Evaluation of a c(RGDyK) Peptide Conjugate of SRPIN803

“…Recent studies show that the combination of antiangiogenic sunitinib with an αvβ3 integrin antagonist cRGDfK peptide displays a synergistic anticancer effect in human lung adenocarcinoma cells . In the present study, SRPIN803 and geo35 were identified to hold antiangiogenic activity in vivo in zebrafish embryos, and this effect was dose-dependent.…”

Combination Effect of Cilengitide with Erlotinib on TGF-β1-Induced Epithelial-to-Mesenchymal Transition in Human Non-Small Cell Lung Cancer Cells

“…Cyclic peptides such as cRGDfK and cRGDyK exhibit high binding affinity and selectivity for the overexpressed integrins α ν β 3 and α ν β 5 in cancer cells, facilitating the delivery of anticancer drugs to the target [ 41 , 42 ]. We recently demonstrated that cRGDfK increased NSCLC apoptosis and enhanced the inhibitory effects of the TKI sunitinib on TGF-β1–induced EMT [ 43 ]. Single compound treatment with TKI involves toxic effects at high concentrations, but in that study, EMT could be effectively inhibited when a cyclic peptide was added to a low concentration of TKI in combined treatment.…”