Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma

Haxho, Fiona; Allison, Stephanie; Alghamdi, Farah; Brodhagen, Lacey; Kuta, Victoria; Abdulkhalek, Samar; Neufeld, Ronald J.; Szewczuk, Myron R.

doi:10.2147/bctt.s74663

Cited by 24 publications

(23 citation statements)

References 38 publications

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“…The prostasphere volume from all the cell lines except PC3 decreased with increasing concentrations of OP. The decrease in spheroid volume could be due to either inhibition of matrix metalloprotease-9 (MMP-9)-mediated cell motility or cytotoxic effect 48,76–78. It was reported that αvβ3 integrin cooperates with MMP-9 in breast cancer cell migration 79.…”

Section: Discussionmentioning

confidence: 99%

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide

Haq¹,

Samuel²,

Haxho³

et al. 2017

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BackgroundProstaspheres-based three dimensional (3D) culture models have provided insight into prostate cancer (PCa) biology, highlighting the importance of cell–cell interactions and the extracellular matrix (EMC) in the tumor microenvironment. Although these 3D classical spheroid platforms provide a significant advance over 2D models mimicking in vivo tumors, the limitations involve no control of assembly and structure with only limited spatial or glandular organization. Here, matrix-free prostaspheres from human metastatic prostate carcinoma PC3 and DU145 cell lines and their respective gemcitabine resistant (GemR) variants were generated by using cyclic Arg-Gly-Asp-D-Phe-Lys peptide modified with 4-carboxybutyl-triphenylphosphonium bromide (cyclo-RGDfK(TPP)).Materials and methodsMicroscopic imaging, immunocytochemistry (ICC), flow cytometry, sialidase, and WST-1 cell viability assays were used to evaluate the formation of multicellular tumor spheroid (MCTS), cell survival, morphologic changes, and expression levels of α2,6 and α2,3 sialic acid (SA) and E- and N-cadherin in DU145, PC3, and their GemR variants.ResultsBy using the cyclo-RGDfK(TPP) peptide platform in a dose- and time-dependent manner, both DU145 and DU145GemR cells formed small MCTS. In contrast, PC3 and PC3GemR cells formed irregular multicellular aggregates at all concentrations of cyclo-RGDfK(TPP) peptide, even after 6 days of incubation. ICC and flow cytometry results revealed that DU145 cells expressed higher amounts of E-cadherin but lower N-cadherin compared with PC3 cells. By using Maackia amurensis (α2,3-SA-specific MAL-II) and Sambucus nigra (α2,6-SA specific SNA) lectin-based cytochemistry staining and flow cytometry, it was found that DU145 and DU145GemR cells expressed 5 times more α2,6-SA than α2,3-SA on the cell surface. PC3 cells expressed 4 times more α2,3-SA than α2,6-SA, and the PC3GemR cells showed 1.4 times higher α2,6-SA than α2,3-SA. MCTS volume was dose-dependently reduced following pretreatment with α2,6-SA-specific neuraminidase (Vibrio cholerae). Oseltamivir phosphate enhanced cell aggregation and compaction of 3D MCTS formed with PC3 cells.ConclusionThe relative levels of specific sialoglycan structures on the cell surface correlate with the ability of PCa cells to form avascular multicellular prostaspheres.

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Section: Discussionmentioning

confidence: 99%

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide

Haq¹,

Samuel²,

Haxho³

et al. 2017

OTT

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“…Both of these compounds are of interest for a variety of industrial applications in food ingredients, pharmaceuticals, and personal care products. The extension to incorporate OP in the formulation of MSPE was examined in the present study for its long-term stability and release to disable human cancer cells survival as previously described [ 7 , 8 , 11 , 13 , 15 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Surgically implanted PLGA-OP containing 20 mg OP and empty PLGA cylinders near the tumor site of heterotopic xenografts of human pancreatic PANC1 cancer cells in RAGxCγ double mutant mice impeded tumor neovascularization, growth rate, and metastatic spread to the liver and lungs compared with the untreated cohort [ 8 ]. Here, OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis [ 9 ] for pancreatic [ 10 ], triple negative breast [ 11 ] and ovarian [ 12 ] cancers. To this end, we engineered and developed OP-conjugated polymeric micelles prepared by RAFT living radical polymerization to target Neu1, which specifically bound Neu1 and activated receptor endocytosis and OP-micelle internalization [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Oseltamivir phosphate released from injectable Pickering emulsions over an extended term disables human pancreatic cancer cell survival

et al. 2018

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Pickering emulsions are colloidal dispersions stabilized by particles that either migrate to, or are formed at, the oil-water interface during emulsification. Here, we fabricated and characterized Pickering water-in-oil emulsions where molten glycerol monostearate crystallized at the surface of micron-sized water droplets and formed protective solid shells. We tested this emulsion as a reservoir delivery platform for the sustained release of low molecular weight hydrophilic molecules including sodium chloride (NaCl) and sodium citrate as model compounds, and the therapeutic oseltamivir phosphate (OP), the delivery of which was the ultimate goal of this research. The objective was to achieve long-term (30-day) release of challenging to encapsulate actives and ultimately demonstrate the sustained release of OP for 20–30 days from an injectable formulation. OP was used because of its anticancer properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. All actives including OP encapsulated in Pickering emulsions displayed a near linear release profile over 30 days. It was demonstrated that the release could be modulated by the addition of a second, competing surfactant sorbitan monooleate, Span 80, to the emulsion at levels above its critical micelle concentration. OP released from the emulsions significantly reduced cell viability in the human PANC-1 pancreatic cancer cell line for up to 30 days. The findings from this study indicate a simple, potentially injectable formulation and method that is easily upscaled resulting in a stable product with the potential to fully retain small hydrophilic molecules/drugs for sustained, near linear release over days, weeks, and potentially months.

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“…Clinical studies show that level of EDP in serum of patients is higher in patients with large tumor size (43). Blocking Neu-1 with oseltamivir phosphate (Tamiflu R ) or a Neu-1 siRNA in mammary carcinoma cells, MCF-7, and MDA-MB-231 cell lines, inhibits cell growth (44). Additional studies also point out an inhibition of tumor neovascularization growth and metastasis under oseltamivir phosphate treatment in mouse model of breast cancer that mimics human triple-negative breast cancer (45).…”

Section: Neu-1 Tm Domain As a Potential Target In Cancersmentioning

confidence: 99%

Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells?

et al. 2020

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Cellular functions are regulated by extracellular signals such as hormones, neurotransmitters, matrix ligands, and other chemical or physical stimuli. Ligand binding on its transmembrane receptor induced cell signaling and the recruitment of several interacting partners to the plasma membrane. Nowadays, it is well-established that the transmembrane domain is not only an anchor of these receptors to the membrane, but it also plays a key role in receptor dimerization and activation. Indeed, interactions between transmembrane helices are associated with specific biological activity of the proteins as cell migration, proliferation, or differentiation. Overexpression or constitutive dimerization (due notably to mutations) of these transmembrane receptors are involved in several physiopathological contexts as cancers. The transmembrane domain of tyrosine kinase receptors as ErbB family proteins (implicated in several cancers as HER2 in breast cancer) or other receptors as Neuropilins has been described these last years as a target to inhibit their dimerization/activation using several strategies. In this review, we will focus on the strategy which consists in using peptides to disturb in a specific manner the interactions between transmembrane domains and the signaling pathways (induced by ligand binding) of these receptors involved in cancer. This approach can be extended to inhibit other transmembrane protein dimerization as neuraminidase-1 (the catalytic subunit of elastin receptor complex), Discoidin Domain Receptor 1 (a tyrosine kinase receptor activated by type I collagen) or G-protein coupled receptors (GPCRs) which are involved in cancer processes.

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Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma

Cited by 24 publications

References 38 publications

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide

Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK(TPP) peptide

Oseltamivir phosphate released from injectable Pickering emulsions over an extended term disables human pancreatic cancer cell survival

Transmembrane Peptides as Inhibitors of Protein-Protein Interactions: An Efficient Strategy to Target Cancer Cells?

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