Protein Binding of a Novel Platinum-Based Anticancer Agent BP-C1 Containing a Lignin-Derived Polymeric Ligand

Platinum (Pt) antineoplastic agents remain indispensable for the treatment of oncological disease. Pt-based drugs are mainly used in the therapy of ovarian cancer and non-small-cell lung carcinoma. A novel platinum-containing antineoplastic agent BP-C1 is a complex of diamminoplatinum with an oxygen-donor polymeric ligand of benzene-polycarboxylic acids, isolated from natural lignin. The aim of the study was to investigate ex vivo protein binding of BP-C1. Protein binding of BP-C1 was tested using equilibrium dialysis. Pooled blood plasma was used in the study. Control solutions contained the same dosages of BP-C1 in PBS (pH 7.2). Plasma and control solutions were submitted to equilibrium dialysis across a vertical 8 kDa cut-off membrane for 4 h at 37 °C under gentle shaking. Platinum was quantified in dialysis and retained fractions using inductively coupled plasma mass spectrometry after microwave digestion. The dialysis system was tested and validated; this showed no protein saturation with platinum. A medium degree of binding of platinum to macromolecular species of ca. 60% was observed. The study showed the maintenance of a high fraction of free BP-C1 in the bloodstream, facilitating its pharmacological activity.

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The Palouse Trial: Pathological Comparison Between in Vivo Lobectomy with Ex Vivo Segmentectomy for Clinically-Staged T1 And T2 Non-Small Cell Lung Carcinoma

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2019.11.417 ◽

2020 ◽

Vol 46 (2) ◽

pp. e158

Author(s):

Michiel Ijsseldijk ◽

Richard ten Broek ◽

Bas Wiering ◽

Ton van Engelenburg ◽

Wout Barendregt ◽

...

Keyword(s):

Lung Carcinoma ◽

Ex Vivo ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

T1 And T2

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Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

Cancer Research ◽

10.1158/0008-5472.can-16-1121 ◽

2017 ◽

Vol 77 (8) ◽

pp. 2029-2039 ◽

Cited By ~ 33

Author(s):

Ellie Karekla ◽

Wen-Jing Liao ◽

Barry Sharp ◽

John Pugh ◽

Helen Reid ◽

...

Keyword(s):

Lung Carcinoma ◽

Primary Tumor ◽

Ex Vivo ◽

Small Cell Lung Carcinoma ◽

Anticancer Therapy ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Explant Cultures

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No-Modified Saquinavir is Equally Efficient Against Doxorubicin Sensitive and Resistant Non-Small Cell Lung Carcinoma Cells / MODIFIKOVANA KOVANA FORMA SAKVINAVIRA EFIKASNO SU PRIMI RA RAST ĆELIJA NESITNOĆELIJSKOG KARCINOMA PLUĆA RAZLIČITE OSETUIVOSTI NA DOKSORUBICIN

Journal of Medical Biochemistry ◽

10.2478/jomb-2013-0050 ◽

2013 ◽

Vol 32 (4) ◽

pp. 406-416 ◽

Cited By ~ 1

Author(s):

Sanja Mijatović ◽

Milica Pešić ◽

Marija Mojić ◽

Jasna Banković ◽

Đorde Miljković ◽

...

Keyword(s):

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Antineoplastic Agent ◽

Small Cell ◽

Carcinoma Cells ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Lung Carcinoma Cells ◽

Hiv Inhibitor

Summary Background: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of can- cer cell lines in vitro and in vivo more potently than the orig- inal compound in a nontoxic fashion. In addition, chemo- and immunosensitizing properties were observed. The aim of the present study was to evaluate its anticancer action against non-small cell lung carcinoma cells in their doxoru- bicin (DOXO) sensitive and resistant phenotype (NCI-H460 and NCI-H460/R). Methods: The viability of cells was analyzed by MTT and crystal violet assays. DR5 expression was estimated by real time RT-PCR and flow cytometry. Activity of P-glycoprotein (P-gp) pumps was evaluated by the Rho123 accumulation assay. Results: Saq-NO diminished the viability of lung cancer cells through induction of cell cycle arrest in the Gq/G1 phase in- dependently of the overexpression of the P-gp pumps. In addition, Saq-NO elevated or completely reconstituted the doxorubicin efficacy in NCI-H460 and NCI-H460/R, respec- tively. The chemosensitizing effect in DOXO resistant cells was a consequence of P-gp inhibition which was found to be more potent than that observed with dex-verapamil, a con- ventional inhibitor of P-gp. Sensitization to DOXO upon Saq- NO was accompanied by elevated DR5 expression, but the resistance to TRAIL was not abrogated. Conclusions: The NO-modified HIV inhibitor saquinavir dis- played equal antiproliferative and chemosensitizing proper- ties in DOXO sensitive and resistant non-small cell lung car- cinoma cells, suggesting the importance of the evaluation of this drug as an antineoplastic agent.

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Multivalent state transitions regulate the intratumoral composition of small cell lung carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20587 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20587-e20587

Author(s):

Priyanka Gopal ◽

Aaron Petty ◽

Rohan Bareja ◽

Titas Bera ◽

Kevin Rogacki ◽

...

Keyword(s):

Single Cell ◽

Lung Carcinoma ◽

Ex Vivo ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Neuroendocrine Cells ◽

State Transitions ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Cell State

e20587 Background: Small cell lung carcinoma (SCLC) is an aggressive, tobacco-associated tumor with neuroendocrine features characterized by rapid growth, metastatic progression, and initial response followed by almost invariable resistance to therapy. Studies to date have not resolved the extent that diverse transcriptional programs drive SCLC and contribute to its lethality. Methods: We combined one of the largest and most diverse inventories of patient-derived xenograft models of SCLC with an ex vivo culture system that maintains transcriptional fidelity with matched primary SCLC tumor to identify transcriptional state heterogeneity. Using the expression of the Ascl1, NeuroD1, and Yap1 as markers of well-conserved SCLC states, we developed a state-of-the-art fluorescent platform that can directly measure single-cell state transitions in a multi-layered ecosystem using tandemly integrated reporters. We modeled population dynamics using a discrete time Markov chain and directly measure single-cell state transitions. Results: We show significant cell-state heterogeneity in several SCLC primary tumors, patient-derived xenografts (PDX), and ex vivo cultures. These states comprise distinct subpopulations marked by the master regulatory transcription factors (TFs) Ascl1, NeuroD1, and Yap1. Ex vivo, the 3 TFs are associated with suspension aggregates of small neuroendocrine cells, pre-suspension (loosely adherent) aggregates, and large mesenchymal cells with visible cytoplasm and spindle-like membrane extensions, respectively. We have observed equilibria in cell-state proportions in SCLC tumors both in vivo (PDX) and ex vivo. In addition, we have shown that the “elasticity” of SCLC responses, measured as the extent of clinical response during chemotherapy followed by the time to relapse from the end of therapy, is dependent on tumor TF levels. These observations suggest that mechanistic modeling of intra-tumoral state dynamics is of high clinical relevance. Conclusions: Our integrative approach is poised to formulate and validate a unified model of cellular states and program diversity in SCLC. If successful, the characterization of malignant cell ontogenic programs, their plasticity, and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming will create a new scientific canvas for the study of this highly lethal disease.

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Dexosomes as a cell-free vaccine for cancer immunotherapy

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01781-x ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Sepideh Nikfarjam ◽

Jafar Rezaie ◽

Fatah Kashanchi ◽

Reza Jafari

Keyword(s):

Cancer Immunotherapy ◽

Immune Cell ◽

Ex Vivo ◽

Small Cell Lung Carcinoma ◽

Costimulatory Molecule ◽

In Vivo Studies ◽

Two Phase ◽

Mhc I ◽

Cell Lung Carcinoma

AbstractDendritic cells (DCs) secrete vast quantities of exosomes termed as dexosomes. Dexosomes are symmetric nanoscale heat-stable vesicles that consist of a lipid bilayer displaying a characteristic series of lipid and protein molecules. They include tetraspanins and all established proteins for presenting antigenic material such as the major histocompatibility complex class I/II (MHC I/II) and CD1a, b, c, d proteins and CD86 costimulatory molecule. Dexosomes contribute to antigen-specific cellular immune responses by incorporating the MHC proteins with antigen molecules and transferring the antigen-MHC complexes and other associated molecules to naïve DCs. A variety of ex vivo and in vivo studies demonstrated that antigen-loaded dexosomes were able to initiate potent antitumor immunity. Human dexosomes can be easily prepared using monocyte-derived DCs isolated by leukapheresis of peripheral blood and treated ex vivo by cytokines and other factors. The feasibility of implementing dexosomes as therapeutic antitumor vaccines has been verified in two phase I and one phase II clinical trials in malignant melanoma and non small cell lung carcinoma patients. These studies proved the safety of dexosome administration and showed that dexosome vaccines have the capacity to trigger both the adaptive (T lymphocytes) and the innate (natural killer cells) immune cell recalls. In the current review, we will focus on the perspective of utilizing dexosome vaccines in the context of cancer immunotherapy.

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Attomole-per Cell Atomic Mass Spectrometry Measurement of Platinum and Gold Drugs in Cultured Lung Cancer Cells

Molecules ◽

10.3390/molecules26247627 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7627

Author(s):

Wioletta Jakubczak ◽

Maja Haczyk-Więcek ◽

Katarzyna Pawlak

Keyword(s):

Metal Ions ◽

Inductively Coupled Plasma ◽

Small Cell Lung Carcinoma ◽

Cross Flow ◽

Transition Metal Ions ◽

Normal Lung ◽

Lower Efficiency ◽

Cell Lung Carcinoma ◽

Drug Concentrations ◽

Inhibitory Drug

In this study, we developed a strategy to determine atto- and femtomolar amounts of metal ions in lysates and mineralizates of cells (human non-small-cell lung carcinoma (NSCLC, A549) and normal lung (MRC-5)) exposed to cytotoxic metallo-drugs: cisplatin and auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC50). The developed strategy combines data obtained using biological and chemical approaches. Cell density was determined using two independent cell staining assays using trypan blue, calcein AM/propidium iodide. Metal concentrations in lysed and mineralized cells were established employing a mass spectrometer with inductively coupled plasma (ICP-MS) and equipped with a cross-flow nebulizer working in aspiration mode. It allowed for detecting of less than 1 fg of metal per cell. To decrease the required amount of sample material (from 1.5 mL to ~100 µL) without loss of sensitivity, the sample was introduced as a narrow band into a constant stream of liquid (flow-injection analysis). It was noticed that the selectivity of cisplatin accumulation by cells depends on the incubation time. This complex is accumulated by cells at a lower efficiency than auranofin and is found primarily in the lysate representing the cytosol. In contrast, auranofin interacts with water-insoluble compounds. Despite their different mechanism of action, both metallo-drugs increased the accumulation of transition metal ions responsible for oxidative stress.

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