Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.

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Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

BMC Pharmacology and Toxicology ◽

10.1186/s40360-019-0369-8 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Yu-chi Shen ◽

Caroline Arellano-Garcia ◽

Rosa E. Menjivar ◽

Ethan M. Jewett ◽

Wolfgang Dohle ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Lines ◽

Tumour Cell ◽

Mechanisms Of Action ◽

Neurofibromatosis 1 ◽

Tumour Suppressor ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Tumour Cell Lines

Abstract Background Neurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2. Methods STX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed. Results Although neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death. Conclusions Both STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.

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The Cytotoxic Effect of Magainin II on the MDA-MB-231 and M14K Tumour Cell Lines

BioMed Research International ◽

10.1155/2013/831709 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Radu Anghel ◽

Daniela Jitaru ◽

Laurenţiu Bădescu ◽

Magda Bădescu ◽

Manuela Ciocoiu

Keyword(s):

Cell Lines ◽

Tumour Cell ◽

Chemotherapeutic Agents ◽

Breast Adenocarcinoma ◽

Public Health Issue ◽

Tumour Cell Line ◽

Global Public Health ◽

Tumour Cell Lines ◽

Magainin Ii

Many studies have highlighted the tumoricidal properties of some natural peptides known to have antimicrobial virtues. Also, the increasingly higher resistance to conventional antibiotics has become a global public health issue, and the need for new antibiotics has stimulated interest in finding and synthesizing new antimicrobial peptides, which may also be used as chemotherapeutic agents. Relying on the literature, the purpose of ourin vitroresearch was to assess the tumoricidal potential of magainin II on a series of tumour cell lines, namely, MDA-MB-231 (breast adenocarcinoma) and M14K (human mesothelioma). The experimental results of our study revealed that the cytotoxic effects of magainin II depend on its concentration. Its efficiency is significant at 120 μM concentrations, and, although it is much lower, it persists even at 60 μM concentrations. The effects were insignificant at 30 μM concentrations. In our experimental research, the tumoricidal effect of magainin II was not significantly dependent on the type of tumour cell line used.

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Screening of Venezuelan medicinal plant extracts for cytostatic and cytotoxic activity against tumour cell lines

Planta Medica ◽

10.1055/s-0032-1320482 ◽

2012 ◽

Vol 78 (11) ◽

Author(s):

P Taylor ◽

M Arsenak ◽

MJ Abad ◽

Á Fernández ◽

R Gonto ◽

...

Keyword(s):

Medicinal Plant ◽

Cytotoxic Activity ◽

Cell Lines ◽

Plant Extracts ◽

Tumour Cell ◽

Medicinal Plant Extracts ◽

Tumour Cell Lines

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Cytotoxic activity against tumour cell lines and anti-inflammatory effects of compounds isolated from Xylopia aromatica

Planta Medica ◽

10.1055/s-0033-1352067 ◽

2013 ◽

Vol 79 (13) ◽

Author(s):

O Estrada ◽

L González ◽

M Mijares ◽

Á Fernández ◽

M Ruiz ◽

...

Keyword(s):

Cytotoxic Activity ◽

Cell Lines ◽

Tumour Cell ◽

Tumour Cell Lines ◽

Anti Inflammatory

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Epigenetic modifiers reduce proliferation of human neuroendocrine tumour cell lines

Endocrine Abstracts ◽

10.1530/endoabs.31.p149 ◽

2013 ◽

pp. 1-1

Author(s):

E Kate Lines ◽

U Katherine Gaynor ◽

Mark Stevenson ◽

J Paul Newey ◽

E Sian Piret ◽

...

Keyword(s):

Cell Lines ◽

Tumour Cell ◽

Neuroendocrine Tumour ◽

Epigenetic Modifiers ◽

Tumour Cell Lines

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Doxorubicin treatment modulates chemoresistance and affects the cell cycle in two canine mammary tumour cell lines

BMC Veterinary Research ◽

10.1186/s12917-020-02709-5 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Michela Levi ◽

Roberta Salaroli ◽

Federico Parenti ◽

Raffaella De Maria ◽

Augusta Zannoni ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Lines ◽

Tumour Cell ◽

S Phase ◽

Mammary Tumour ◽

Cancer Resistance ◽

Neoplastic Cells ◽

Canine Mammary Tumour ◽

Tumour Cell Lines

Abstract Background Doxorubicin (DOX) is widely used in both human and veterinary oncology although the onset of multidrug resistance (MDR) in neoplastic cells often leads to chemotherapy failure. Better understanding of the cellular mechanisms that circumvent chemotherapy efficacy is paramount. The aim of this study was to investigate the response of two canine mammary tumour cell lines, CIPp from a primary tumour and CIPm, from its lymph node metastasis, to exposure to EC50(20h) DOX at 12, 24 and 48 h of treatment. We assessed the uptake and subcellular distribution of DOX, the expression and function of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), two important MDR mediators. To better understand this phenomenon the effects of DOX on the cell cycle and Ki67 cell proliferation index and the expression of p53 and telomerase reverse transcriptase (TERT) were also evaluated by immunocytochemistry (ICC). Results Both cell lines were able to uptake DOX within the nucleus at 3 h treatment while at 48 h DOX was absent from the intracellular compartment (assessed by fluorescence microscope) in all the surviving cells. CIPm, originated from the metastatic tumour, were more efficient in extruding P-gp substrates. By ICC and qRT-PCR an overall increase in both P-gp and BCRP were observed at 48 h of EC50(20h) DOX treatment in both cell lines and were associated with a striking increase in the percentage of p53 and TERT expressing cells by ICC. The cell proliferation fraction was decreased at 48 h in both cell lines and cell cycle analysis showed a DOX-induced arrest in the S phase for CIPp, while CIPm had an increase in cellular death without arrest. Both cells lines were therefore composed by a fraction of cells sensible to DOX that underwent apoptosis/necrosis. Conclusions DOX administration results in interlinked modifications in the cellular population including a substantial effect on the cell cycle, in particular arrest in the S phase for CIPp and the selection of a subpopulation of neoplastic cells bearing MDR phenotype characterized by P-gp and BCRP expression, TERT activation, p53 accumulation and decrease in the proliferating fraction. Important information is given for understanding the dynamic and mechanisms of the onset of drug resistance in a neoplastic cell population.

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