Synergistic Anti-Tumor Effect of Cisplatin When Combined with an Anti-Src Kinase Integrin-Based Peptide

Agrez, Michael; Garg, Mukesh; Dorahy, Douglas J.; Ackland, Stephen P.

doi:10.4236/jct.2011.23039

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…6 c). Given that SFK members share a common domain structure 68 and that RSKAKNPLYR has previously been reported to inhibit c-Src activity 53 we next sought to compare the effects of IK14004, RSKAKNPLYR (IK14000) and the dodecanoic acid moiety (IK00041) on the activity of c-Src using a non-cell-based kinase profiling approach. A combination of peptide plus dodecanoic acid, i.e., IK14004, was the most effective inhibitor of c-Src activity at concentrations below 3 µM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, targeting calcineurin-dependent NFAT signalling pathways and JAK/STATs have become attractive options against autoimmune diseases 51 , 52 . We have previously reported that an ERK-binding peptide, RSKAKNPLYR, inhibits c-Src activity 53 . Linkages between a peptide drug and a branched lipid unit are thought to enhance drug stability and generate a membrane-like structure with increased lipophilicity 54 .…”

Section: Introductionmentioning

confidence: 99%

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A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses

Agrez¹,

Rzepecka

Turner

et al. 2022

Sci Rep

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T cell-dendritic cell (DC) interactions contribute to reciprocal stimulation leading to DC maturation that results in production of interleukin-12 (IL-12) and interferon-gamma (IFN-γ). Both cytokines have been implicated in autoimmune diseases while being necessary for effective immune responses against foreign antigens. We describe a lipidic peptide, designated IK14004, that modifies crosstalk between T cells and DCs resulting in suppression of IL-12p40/IFN-γ production. T cell production of interleukin-2 (IL-2) and IFN-γ is uncoupled and IL-12p70 production is enhanced. IK14004 induces expression of activating co-receptors in CD8+ T cells and increases the proportion of Foxp3-expressing CD4+ T regulatory cells. The potential for IK14004 to impact on signalling pathways required to achieve a balanced immune response upon stimulation of DCs and T cells is highlighted. This novel compound provides an opportunity to gain further insights into the complexity of T cell-DC interactions relevant to autoimmunity associated with malignancies and may have therapeutic benefit.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses

Agrez¹,

Rzepecka

Turner

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…

Background:The NPxY motif common to all β integrin cytoplasmic domains forms part of a canonical recognition sequence for phosphotyrosine-binding domains which are protein modules present in a wide variety of signaling and cytoskeletal proteins. We have recently reported that a non-naturally occurring peptide, RSKAKNPLYR, derived from the β6 integrin cytoplasmic domain inhibits cancer cell growth in vitro and proposed that this may be due, at least in part, to the inhibition of c-Src activity [1]. In the present study we examined the role of the NPLY motif within RSKAKNPLYR in terms of its requirement for inhibition of cancer cell growth.

…”

mentioning

confidence: 94%

“…We have previously reported that a sequence of 15 amino acids, RSK-AKWQTGTNPLYR, located within the cytoplasmic tail of the β6 integrin subunit binds to extracellular signal-regulated kinase 2 (ERK2) and proposed that this contributes to tumor growth [5]. More recently, we reported that a novel peptide, RSKAKNPLYR, derived from the β6 binding sequence inhibits cancer cell growth in vitro and proposed that this may be due, in part at least, to the inhibition of c-Src activity [1].…”

Section: Introductionmentioning

confidence: 99%

Novel Anti-Cancer Peptides Comprising Three Amino Acids

Agrez¹,

Garg²,

Ackland³

2012

JCT

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Background: The NPxY motif common to all β integrin cytoplasmic domains forms part of a canonical recognition sequence for phosphotyrosine-binding domains which are protein modules present in a wide variety of signaling and cytoskeletal proteins. We have recently reported that a non-naturally occurring peptide, RSKAKNPLYR, derived from the β6 integrin cytoplasmic domain inhibits cancer cell growth in vitro and proposed that this may be due, at least in part, to the inhibition of c-Src activity [1]. In the present study we examined the role of the NPLY motif within RSKAKNPLYR in terms of its requirement for inhibition of cancer cell growth. Materials and Methods: The effects of peptide modifications to RSKAKNPLYR on in vitro proliferation of human cancer cell lines (colorectal HT29, prostate DU145, breast MCF-7 and ovarian A2780) were evaluated using the MTT cell growth assay. Passage of peptide across the plasma membrane was assessed by means of confocal microscopy using FITC-labelled peptide. The effect of peptide on kinase activity was assessed in cell-free in vitro kinase assays. Results: The NPLY motif within RSKAKNPLYR was found to be essential for the growth inhibitory effect of this peptide. However, modified forms of this peptide in which all amino acids except the charged residues arginine and lysine were replaced by single non-polar amino acids such as alanine or valine were equally effective at inhibiting cancer cell proliferation. Moreover, these peptides inhibited not only c-Src activity as seen for RSKAKNPLYR but also the activity of members of the PKB/Akt kinase family. Conclusion: Novel decapeptides comprising only three amino acids have anti-cancer effects without the requirement for an integrin-based NPLY motif. These peptides inhibit the activity of not only c-Src but also members of the Akt family of kinases and may be useful as potential anti-cancer agents when used either alone or in combination with compounds previously reported to inhibit c-Src kinase activity

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An immunomodulating peptide to counteract solar radiation-induced immunosuppression and DNA damage

Agrez

Rybchyn

Silva

et al. 2023

Sci Rep

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Ultraviolet radiation (UVR) induces immunosuppression and DNA damage, both of which contribute to the rising global incidence of skin cancer including melanoma. Nucleotide excision repair, which is activated upon UVR-induced DNA damage, is linked to expression of interleukin-12 (IL-12) which serves to limit immunosuppression and augment the DNA repair process. Herein, we report an immunomodulating peptide, designated IK14800, that not only elicits secretion of IL-12, interleukin-2 (IL-2) and interferon-gamma (IFN-γ) but also reduces DNA damage in the skin following exposure to UVR. Combined with re-invigoration of exhausted CD4+ T cells, inhibition of UVR-induced MMP-1 release and suppression of B16F10 melanoma metastases, IK14800 offers an opportunity to gain further insight into mechanisms underlying the development and progression of skin cancers.

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Synergistic Anti-Tumor Effect of Cisplatin When Combined with an Anti-Src Kinase Integrin-Based Peptide

Abstract: Background: It is known that active Src kinase promotes survival of ovarian cancer cell lines and inhibition of c-

Cited by 5 publications

References 28 publications

A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses

A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses

Novel Anti-Cancer Peptides Comprising Three Amino Acids

An immunomodulating peptide to counteract solar radiation-induced immunosuppression and DNA damage

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