Overcoming Cancer Cell Drug Resistance by a Folic Acid Targeted Polymeric Conjugate of Buthionine Sulfoximine

2019 ◽  
Vol 19 (12) ◽  
pp. 1513-1522 ◽  
Author(s):  
Felisa Cilurzo ◽  
Maria C. Cristiano ◽  
Marta Da Pian ◽  
Eleonora Cianflone ◽  
Luigi Quintieri ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Folate Receptor ◽  
Buthionine Sulfoximine ◽  
Low Molecular Weight ◽  
Irreversible Inhibitor ◽  
Glutamate Cysteine Ligase ◽  
Cancer Chemotherapeutics ◽  
Polymeric Conjugate

Background:Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH in vitro and in in vivo and sensitizes tumor cells to radiation and some cancer chemotherapeutics, its toxicity and short in vivo half-life have limited its application to combination anticancer therapies.Objective:To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH.Methods:A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor.Results:The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor.Conclusion:The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine.

scholarly journals Biodegradable Nanoparticles Combining Cancer Cell Targeting and Anti-Angiogenic Activity for Synergistic Chemotherapy in Epithelial Cancer

2021 ◽  
Author(s):  
Francesca moret ◽  
Claudia Conte ◽  
Diletta Esposito ◽  
Giovanni Dal Poggetto ◽  
Concetta Avitabile ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Folate Receptor ◽  
Tube Formation ◽  
Multicellular Spheroids ◽  
Angiogenic Activity ◽  
Biodegradable Nanoparticles ◽  
Therapeutic Concepts ◽  
Poly Ethylene

Abstract A biodegradable engineered nanoplatform combining anti-angiogenic activity and targeting of cancer cells to improve the anticancer activity of docetaxel (DTX) is here proposed. Indeed, we have developed biodegradable nanoparticles (NPs) of poly(ethylene glycol)-poly(ε-caprolactone), exposing on the surface both folate motifs (Fol) for recognition in cells overexpressing Folate Receptor- a (FRa) and the anti-angiogenic hexapeptide aFLT1. The presence of Fol on NPs did not impair the anti-angiogenic activity of aFLT1, as assessed by in vitro tube formation assay in HUVEC endothelial cells. In both 2D and 3D KB cell cultures in vitro , the cytotoxicity of DTX loaded in NPs was not significantly affected by Fol/aFLT1 double decoration as compared to free DTX. Remarkably, NPs distributed differently in 3D multicellular spheroids of FRa-positive KB cancer cells depending on the type of ligand displayed on the surface. When tested in vivo in zebrafish embryos xenografted with KB cells, NPs displaying Fol/aFLT1 reduced DTX systemic toxicity and inhibited in a synergistic way the growth of the tumor mass and associated vasculature. Overall, nanotechnology offers excellent ground for combining therapeutic concepts in cancer, paving the way to the development of novel multifunctional nanopharmaceuticals where surface decoration with bioactive elements can significantly improve therapeutic outcomes.

scholarly journals Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles: in vitro and in vivo investigations

2016 ◽  
Vol 14 (1) ◽  
Author(s):  
Hamidreza Fasehee ◽  
Rassoul Dinarvand ◽  
Ardeshir Ghavamzadeh ◽  
Mehdi Esfandyari-Manesh ◽  
Hanieh Moradian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Folate Receptor

scholarly journals Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization

2017 ◽  
Vol 10 (4) ◽  
pp. 72 ◽  
Author(s):  
Klaudia Siwowska ◽  
Raffaella Schmid ◽  
Susan Cohrs ◽  
Roger Schibli ◽  
Cristina Müller
Keyword(s):  
Cancer Cells ◽  
Folate Receptor ◽  
Gynecological Cancer ◽  
In Vivo Characterization

Effects of Unfractionated and Low Molecular Weight Heparins on Platelet Thromboxane Biosynthesis “In Vivo”

1994 ◽  
Vol 72 (06) ◽  
pp. 942-946 ◽  
Author(s):  
Raffaele Landolfi ◽  
Erica De Candia ◽  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Armando Antinori ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Primary Source ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
Heparin Administration ◽  
To Receive

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

1986 ◽  
Vol 56 (03) ◽  
pp. 318-322 ◽  
Author(s):  
V Diness ◽  
P B Østergaard
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Protamine Sulfate ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

In Vitro and In Vivo Antitumor Efficacy of Docetaxel and Sorafenib Combination in Human Pancreatic Cancer Cells

2010 ◽  
Vol 999 (999) ◽  
pp. 1-11
Author(s):  
P. Ulivi ◽  
C. Arienti ◽  
W. Zoli ◽  
M. Scarsella ◽  
S. Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Antitumor Efficacy ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

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