Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells

Böhme, David; Krieghoff, Jan; Beck‐Sickinger, Annette G.

doi:10.1021/acs.jmedchem.6b00043

Cited by 38 publications

(23 citation statements)

References 36 publications

(94 reference statements)

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“…For hY 1 R, a number of selective full‐length ligands with 36 amino acids have been reported, most prominently [Phe 7 ,Pro 34 ]NPY . Since 2001, hY 1 R has been known to be overexpressed in breast tumour tissue, making selective agonists even more relevant for use as shuttles for the site‐specific delivery of cytotoxic drugs . The preference of an agonist over an antagonist for that purpose lies in the ability of the agonist to induce internalisation of the receptor–peptide complex, thereby delivering the conjugated drug into the cell .…”

Section: Discussionmentioning

confidence: 99%

“…The preference of an agonist over an antagonist for that purpose lies in the ability of the agonist to induce internalisation of the receptor–peptide complex, thereby delivering the conjugated drug into the cell . For [Phe 7 ,Pro 34 ]NPY, this was already successfully applied by conjugation of cytotoxic tubulysin‐derived peptides or methotrexate, both of which were selectively delivered into hY 1 R‐overexpressing (tumour) cells and induced apoptosis. Another approach was the coupling of carbaborane clusters to agonist peptides to enhance the boron concentration in tumour cells for boron neutron capture therapy .…”

Section: Discussionmentioning

confidence: 99%

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Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism

et al. 2018

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The human Y receptor is overexpressed in breast tumour cells and is, therefore, a valuable target for site-selective drug delivery. The well-established hY R-selective ligand [Phe7,Pro34]NPY has been used to couple to drugs but its length of 36 amino acids also implies complex synthesis and high production costs. Therefore, shorter ligands are desirable. However, truncated versions of neuropeptide Y (NPY) usually result in reduced binding, antagonists, or only partial G-protein-biased agonists. Herein, we report on a nonamer peptide derived from the C terminus of NPY that is modified by a carbaborane, which is able to activate hY R fully in terms of G-protein activation but also arrestin recruitment and internalisation. We provide evidence that this unique behaviour is due to the bulky nature of the carbaborane cluster, which might address a specific second binding pocket in hY R that is crucial for arrestin recruitment. Thus, this study helps in deciphering ligand-induced onset of different pathways in hY R mediated signalling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism

et al. 2018

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“…MTX is the most commonly used disease-modifying anti-rheumatic agent and is also effective at treating patients with breast cancer ( 28 , 29 ). Previous studies have demonstrated that MTX induces greater cytotoxicity and growth inhibition in leukemia and other malignant cell types compared with other treatments ( 30 , 31 ). It has been demonstrated that sustained ERS is a major contributor to MTX-induced cell death, as indicated by the induction of several unfolded protein response markers, which ultimately induce apoptosis ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Methotrexate remediates spinal cord injury inï¿½vivo and inï¿½vitro via suppression of endoplasmic reticulum stress-induced apoptosis

et al. 2018

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It has been suggested that endoplasmic reticulum stress (ERS) may induce apoptosis following spinal cord injury (SCI). Methotrexate (MTX) has been used as a long-term therapy regimen for rheumatoid arthritis. However, it is not clear whether MTX remediates SCI by inhibiting ERS. In the present study, to establish an in vitro ERS cell model, PC12 cells were pre-incubated with triglycerides (TG). MTT assays revealed that treatment with 1, 2.5, 5 and 10 µM TG decreased PC12 cell viability in a dose-dependent manner. Additionally, MTX treatment significantly reversed the TG-induced decrease in cell viability and increased apoptosis according to the flow cytometry assay (P<0.05). Notably, western blotting indicated that MTX significantly decreased levels of glucose-regulated protein (GRP)78, CCAAT-enhancer-binding protein homologous protein (CHOP) and caspase-12 expression (P<0.05), which were increased following treatment with TG. Furthermore, the in vivo role of MTX in a rat model of SCI was evaluated. The motor behavioral function of rats was improved following treatment with MTX according to Basso, Beattie and Bresnahan scoring (P<0.05). Terminal deoxynucleotidyl-transferase-mediated dUTP nick end staining indicated that there were no apoptotic cells present in sham rats. In the SCI model group, apoptotic cells were observed at day 7; however, the number of apoptotic cells was reduced following an additional 7 days of MTX administration. Furthermore, levels of ERS-associated proteins, including caspase-3, activating transcription factor 6, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α, eukaryotic initiation factor 2 α and GRP78, were significantly increased following SCI; however, administration of MTX for 7 days significantly reversed this effect (P<0.05, P<0.01 and P<0.001). Therefore, MTX may improve SCI by suppressing ERS-induced apoptosis in vitro and in vivo.

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“…A follow‐up study intended to increase the toxicity of the NPY‐based PDC by doubling the amount of toxophores. [ 188 ] Therefore, MTX was simultaneously conjugated to the side‐chains of Lys 4 and the inserted Lys 22 in [F 7 ,P 34 ]‐NPY via GFLG‐linkers, resulting in the double‐modified PDC [K 4 (GFLG‐MTX),F 7 ,K 18 (GFLG‐MTX),P 34 ]‐NPY. A higher cytotoxic effect of the double‐MTX PDC compared to single‐MTX PDCs was obtained on various hY 1 R‐rexpressing breast cancer cell lines.…”

Section: Variation Of the Drug Cargo In Receptor‐targeting Peptide‐drmentioning

confidence: 99%

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

2020

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Specifically addressing cell surface molecules on cancer cells facilitates targeted cancer therapies that offer the potential to selectively destroy malignant cells, while sparing healthy tissue. Thus, undesired side-effects in tumor patients are highly reduced. Peptide-binding receptors are frequently overexpressed on cancer cells and therefore promising targets for selective tumor therapy. In this review, peptidebinding receptors for anti-cancer drug delivery are summarized with a focus on peptide ligands as delivery agents. In the first part, some of the most studied peptidebinding receptors are presented, and the ghrelin receptor and the Y 1 receptor are introduced as more recent targets for cancer therapy. Furthermore, nonpeptidic small molecules for receptor targeting on cancer cells are outlined. In the second part, peptide conjugates for the delivery of therapeutic cargos in cancer therapy are described.The essential properties of receptor-targeting peptides are specified, and recent developments in the fields of classical peptide-drug conjugates with toxic agents, radiolabeled peptides for radionuclide therapy, and boronated peptides for boron neutron capture therapy are presented. K E Y W O R D SBNCT, G protein-coupled receptor, internalization, peptide drug conjugate, tumor targeting

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Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells

Cited by 38 publications

References 36 publications

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism

Methotrexate remediates spinal cord injury inï¿½vivo and inï¿½vitro via suppression of endoplasmic reticulum stress-induced apoptosis

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

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Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells

Cited by 38 publications

References 36 publications

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY1 Receptor Agonism

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY1 Receptor Agonism

Methotrexate remediates spinal cord injury inï¿½vivo and inï¿½vitro via suppression of endoplasmic reticulum stress-induced apoptosis

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

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Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism

Carbaboranylation of Truncated C‐Terminal Neuropeptide Y Analogue Leads to Full hY₁ Receptor Agonism