scholarly journals Bauhinia variegata candida Fraction Induces Tumor Cell Death by Activation of Caspase-3, RIP, and TNF-R1 and Inhibits Cell Migration and Invasion In Vitro

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
K. M. Santos ◽  
I. N. F. Gomes ◽  
R. J. Silva-Oliveira ◽  
F. E. Pinto ◽  
B. G. Oliveira ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Migration And Invasion ◽  
Cytotoxic Action ◽  
Tumor Cell Death ◽  
Peripheral Blood Mononuclear ◽  
Cell Migration And Invasion ◽  
Bauhinia Variegata

Metastasis remains the most common cause of death in cancer patients. Inhibition of metalloproteinases (MMPs) is an interesting approach to cancer therapy because of their role in the degradation of extracellular matrix (ECM), cell-cell, and cell-ECM interactions, modulating key events in cell migration and invasion. Herein, we show the cytotoxic and antimetastatic effects of the third fraction (FR3) from Bauhinia variegata candida (Bvc) stem on human cervical tumor cells (HeLa) and human peripheral blood mononuclear cells (PBMCs). FR3 inhibited MMP-2 and MMP-9 activity, indicated by zymogram. This fraction was cytotoxic to HeLa cells and noncytotoxic to PBMCs and decreased HeLa cell migration and invasion. FR3 is believed to stimulate extrinsic apoptosis together with necroptosis, assessed by western blotting. FR3 inhibited MMP-2 activity in the HeLa supernatant, differently from the control. The atomic mass spectrometry (ESI-MS) characterization suggested the presence of glucopyranosides, D-pinitol, fatty acids, and phenolic acid. These findings provide insight suggesting that FR3 contains components with potential tumor-selective cytotoxic action in addition to the action on the migration of tumor cells, which may be due to inhibition of MMPs.

Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3439-3447 ◽  
Author(s):  
Francesco Parlati ◽  
Susan J. Lee ◽  
Monette Aujay ◽  
Erika Suzuki ◽  
Konstantin Levitsky ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mononuclear Cells ◽  
Proteasome Inhibitors ◽  
Selective Inhibition ◽  
Tumor Cell Death ◽  
Clinical Safety ◽  
Peripheral Blood Mononuclear ◽  
Non Hodgkin Lymphoma ◽  
Proteasome Subunits ◽  
The Impact

Abstract Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits β5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells. Although specific inhibition of either LMP7 or β5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both β5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2α suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors.

Activation Of EphrinB2/EphB4 Influences Myeloid Leukemia Cell Migration and Invasion

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1360-1360
Author(s):  
Xuan Zhou ◽  
Liu Xiaoli ◽  
Na Xu ◽  
Yajuan Xiao ◽  
Jinfang Zhang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Leukemia Cell ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Healthy Donors ◽  
Myeloid Leukemia Cell

Abstract Eph receptors and ephrin ligands are cell-surface molecules capable of bidirectional signaling that control cell-cell interactions, migration and invasion. However, their role and regulation in myeloid leukemia cells remain to be defined. To address the hypothesis that Ephrin/EphB is an important regulator of myeloid leukemia cell migration and invasion, we first screened the mRNA levels of 23 eph and ligand ephrin RTK family members in myeloid leukemia cells (K562, HL-60, THP-1) and mononuclear cells from healthy donors, then found that EphB4, EphA5, EfnA1 highly expressed in most myeloid leukemia cells compared to healthy donors(P<0.05). Both the mRNA and protein levels of EphB4 and EphA5 were detected in 13 primary myeloid leukemia cells (5 from patients with extramedullary leukemia among 13 cases) and 10 mononuclear cells from healthy donors by real-time RT-PCR and Immunoblot analysis. The results showed that both the mRNA and protein levels of EphB4 and EphA5 were higher in 13 primary myeloid leukemia cells relative to the 10 healthy donors (P=0.046). Moreover, the EphB4 were highly expressed in 5 patients with extramedullary leukemia compared with 8 patients without extramedullary leukemia. These findings indicated that EphB4 and EphA5 expression were correlated with the development of myeloid leukemia cells, moreover, EphB4 may be closely related with myeloid leukemia cell migration or invasion. To further clarified the question, migration were determined in leukemia cell lines (K562 cells) which were treated with clustered ephrinA1–Fc proteins, ephrinB2–Fc proteins and Fc proteins by transwell migration assay. Invasion were also determined by matrigel invasion assay. The results showed that, after ephrinB2–Fc stimulation, the numbers of K562 cells migrating through transwell chamber were significantly enhanced compared to Fc proteins stimulation (1.8 to 2.5-fold, P<0.05), meanwhile, the numbers of K562 cells invading the matrigel also enhanced (1.2 to 1.8-fold, P<0.05). However, after ephrinA1–Fc stimulation, the numbers of K562 cells migrating through transwell chamber didn’t significantly increase compared to Fc proteins stimulation (P>0.05), and the numbers of K562 cells invading the matrigel also didn’t enhanced (P>0.05). These findings indicated that ephrinB2–Fc could activate EphB4, leading to the change of myeloid leukemia cell migration and invasion. Further study may help to assess a promising potential of this protein to be used as a prognostic marker or as a target for a molecular therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene.

1992 ◽  
Vol 175 (1) ◽  
pp. 217-225 ◽  
Author(s):  
M R Shalaby ◽  
H M Shepard ◽  
L Presta ◽  
M L Rodrigues ◽  
P C Beverley ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Human Tumor ◽  
Cytotoxic Activities ◽  
Cytotoxic Lymphocytes ◽  
Peripheral Blood Mononuclear ◽  
Antibody Molecule ◽  
Human T Cells

The HER2 protooncogene encodes a 185-kD transmembrane phosphoglycoproteins, human epidermal growth factor receptor 2 (p185HER2), whose amplified expression on the cell surface can lead to malignant transformation. Overexpression of HER2/p185HER2 is strongly correlated with progression of human ovarian and breast carcinomas. Recent studies have shown that human T cells can be targeted with bispecific antibody to react against human tumor cells in vitro. We have developed a bispecific F(ab')2 antibody molecule consisting of a humanized arm with a specificity to p185HER2 linked to another arm derived from a murine anti-CD3 monoclonal antibody that we have cloned from UCHT1 hybridoma. The antigen-binding loops for the anti-CD3 were installed in the context of human variable region framework residues, thus forming a fully humanized BsF(ab')2 fragment. Additional variants were produced by replacement of amino acid residues located in light chain complementarity determining region 2 and heavy chain framework region 3 of the humanized anti-CD3 arm. Flow cytometry analysis showed that the bispecific F(ab')2 molecules can bind specifically to cells overexpressing p185HER2 and to normal human peripheral blood mononuclear cells bearing the CD3 surface marker. In additional experiments, the presence of bispecific F(ab')2 caused up to fourfold enhancement in the cytotoxic activities of human T cells against tumor cells overexpressing p185HER2 as determined by a 51Cr release assay. These bispecific molecules have a potential use as therapeutic agents for the treatment of cancer.

scholarly journals Antitumoral and Immunomodulatory Effect of Mahonia aquifolium Extracts

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Andra Diana Andreicuț ◽  
Eva Fischer-Fodor ◽  
Alina Elena Pârvu ◽  
Adrian Bogdan Ţigu ◽  
Mihai Cenariu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Lymphocyte Activation ◽  
Interleukin 10 ◽  
Peripheral Blood Mononuclear ◽  
Mahonia Aquifolium

The prodrug potential of Mahonia aquifolium, a plant used for centuries in traditional medicine, recently gained visibility in the literature, and the activity of several active compounds isolated from its extracts was studied on biologic systems in vitro and in vivo. Whereas the antioxidative and antitumor activities of M. aquifolium-derived compounds were studied at some extent, there are very few data about their outcome on the immune system and tumor cells. To elucidate the M. aquifolium potential immunomodulatory and antiproliferative effects, the bark, leaf, flower, green fruit, and ripe fruit extracts from the plant were tested on peripheral blood mononuclear cells and tumor cells. The extracts exert fine-tuned control on the immune response, by modulating the CD25 lymphocyte activation pathway, the interleukin-10 signaling, and the tumor necrosis-alpha secretion in four distinct human peripheral blood mononuclear cell (PBMC) subpopulations. M. aquifolium extracts exhibit a moderate cytotoxicity and changes in the signaling pathways linked to cell adhesion, proliferation, migration, and apoptosis of the tumor cells. These results open perspectives to further investigation of the M. aquifolium extract prodrug potential.

scholarly journals PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice

2017 ◽  
Vol 114 (52) ◽  
pp. 13655-13660 ◽  
Author(s):  
Yael Langut ◽  
Alaa Talhami ◽  
Samarasimhareddy Mamidi ◽  
Alexei Shir ◽  
Maya Zigler ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mononuclear Cells ◽  
Tumor Regression ◽  
Human Peripheral Blood ◽  
Surface Membrane ◽  
Severe Combined Immunodeficiency ◽  
Complete Regression ◽  
Systemic Delivery ◽  
Tumor Cell Death ◽  
Antitumor Effects

There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine–polyethyleneglycol (PEI–PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.

scholarly journals Circulating Myeloid-derived Suppressor Cells Facilitate Invasion of Thyroid Cancer Cells by Repressing miR-486-3p

2020 ◽  
Vol 105 (8) ◽  
pp. 2704-2718
Author(s):  
Li Chen ◽  
Li Xiong ◽  
Shubing Hong ◽  
Jin Li ◽  
Zijun Huo ◽  
...  
Keyword(s):  
Cell Migration ◽  
Thyroid Cancer ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Migration And Invasion ◽  
Myeloid Derived Suppressor Cells ◽  
Messenger Rnas ◽  
Peripheral Blood Mononuclear

Abstract Background Myeloid-derived suppressor cells (MDSCs) have become increasingly recognized as facilitators of tumor development. However, the role of MDSCs in papillary thyroid carcinoma (PTC) progression has not been clearly explored. Objective We aimed to evaluate the levels and function of circulating MDSCs in PTC. Methods The proportion of circulating polymorphonuclear (PMN)-MDSCs and mononuclear-MDSCs from patients with PTC or benign thyroid nodules and healthy controls was measured using flow cytometry. For immunosuppressive activity analysis, sorted circulating MDSCs were cocultured with CD3/CD28-costimulated T lymphocytes and the proliferation of T cells was determined. PTC cell lines (TPC-1 and BC-PAP) were cocultured with PMN-MDSCs, and the effects on cell migration, invasion, proliferation, and apoptosis were evaluated. The differential expressed microribonucleic acids (RNAs) and messenger RNAs and their function were also explored in TPC-1 cells cocultured with or without PMN-MDSCs. Results PMN-MDSCs were increased in peripheral blood mononuclear cells of patients with PTC. Circulating PMN-MDSCs displayed strong T cell suppressive activity. PTC cells demonstrated enhanced invasive capabilities in vitro and in vivo when cocultured with sorted PMN-MDSCs. PMN-MDSCs decreased expression of miR-486-3p and activated nuclear factor kappa B2 (NF-κB2), a direct target of miR-486-3p. Rescue of miR-486-3p diminished the cell migration and invasion induced by PMN-MDSCs. Conclusion Collectively, our work indicates that circulating PMN-MDSCs promote PTC progression. By suppressing miR-486-3p, PMN-MDSCs promote the activity of the NF-κB2 signaling pathway, resulting in accelerated invasion of PTC cells, which may provide new therapeutic strategies for treatment of thyroid cancer.

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