Dual-acting antitumor Pt(iv) prodrugs of kiteplatin with dichloroacetate axial ligands

2018 ◽  
Vol 47 (21) ◽  
pp. 7144-7158 ◽  
Author(s):  
Salvatore Savino ◽  
Valentina Gandin ◽  
James D. Hoeschele ◽  
Cristina Marzano ◽  
Giovanni Natile ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Biologically Active ◽  
Axial Ligands

DNA and mitochondria of tumor cells are the targets of Pt(iv) complexes of kiteplatin with biologically active dichloroacetate as axial ligands.

Identification of biologically active cancer cells in blood and bone marrow of cancer patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1001-1001 ◽  
Author(s):  
C. Panabières ◽  
J. Vendrell ◽  
O. Pellé ◽  
X. Rebillard ◽  
S. Riethdorf ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Specific Antigen ◽  
Biologically Active ◽  
Breast Cancer Patients ◽  
Mucin 1 ◽  
Epithelial Tumor

1001 Background: Metastasis is the main cause of cancer-related death. Single disseminated tumor cells (DTC) can be detected by sensitive immunocytochemical and molecular technologies, but it is still unclear whether these cells are viable and biologically active. Methods: We applied a novel enzyme-linked immunospot assay (‘EPISPOT‘) that reveals a fingerprint of specific proteins secreted from single viable epithelial tumor cells. The membrane of ELISPOT plates were coated with monoclonal antibodies against the tumor-associated marker proteins mucin-1 (MUC1) for breast cancer and prostate-specific antigen (PSA) for prostate cancer. In addition, dual fluorescent EPISPOT assays were developed to characterize MUC1+ and PSA+ cells (i.e. CK19, FGF2 secretion). Results: Even in the absence of overt metastases (stage M0), the EPISPOT assay revealed viable tumor cells in the peripheral blood of 65% of prostate cancer patients (n=31) and the bone marrow of 54% of breast cancer patients (n=37). Respective samples from non-carcinoma controls were EPISPOT- negative, whereas 80 to 100% of samples from metastatic patients (stage M1, n=40) were positive. The number of EPISPOT-positive cells in M0-patients ranged from 2 to 197 in the blood of prostate cancer patients and 1 to 262 in the bone marrow of breast cancer patients, while M1- patients showed significantly higher counts (prostate cancer, 1–684; breast cancer, 4–813). Interestingly, subsets of MUC1- or PSA-secreting cells expressed a breast stem cell-like phenotype (MUC1-/CK19+) or secreted FGF-2 as factor relevant for the growth of DTC, respectively. Conclusions: A significant fraction of cancer patients harbor viable and biologically active tumor cells in their blood and bone marrow, even in the absence of overt metastases. The multiparameter EPISPOT assay helps to identify these putative metastatic precursor cells. No significant financial relationships to disclose.

In vitro chemosensitivity testing of mammospheres cultured from circulating epithelial tumor cells (CETCs) of breast cancer patients: Comparision to chemosensitivity of total CETCs.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 50-50
Author(s):  
Monika Pizon ◽  
Dorothea Zimon ◽  
Ulrich A. Pachmann ◽  
Katharina Pachmann
Keyword(s):  
Suspension Culture ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
White Blood Cells ◽  
Biologically Active ◽  
Epithelial Tumor ◽  
Chemosensitivity Testing ◽  
In Vitro Chemosensitivity ◽  
Epithelial Tumor Cells

50 Background: In vitro chemosensitivity testing of circulating epithelial tumor cells (CETCs) provides real-time information about the sensitivity of the tumor cells present in the patient. Nevertheless, a fraction of CETCs can survive after conventional chemotherapy and grow into distant metastasis. This may be a subpopulation of CETCs with proliferation activity which has the ability to form floating spheres in suspension culture. Spheroids exhibit stem cell-like properties and may be responsible for chemotherapeutic resistance. Therefore, the aim of our study was to determine the efficacy of chemotherapeutics on spheroids cultured from CETCs. Methods: The enumeration of CETCs from patients with solid tumors in clinical stage I to IV was performed using the maintrac method. Subsequently, CETCs in the context of the surrounding white blood cells were cultured in a suspension culture allowing for spheroid formation. To evaluate the cytotoxic effect of drugs on CETCs and spheroids we exposed them to anticancer drugs in short time culture in different concentrations and for different periods of time. Results: In contrast to CETCs, spheroids were significantly more chemotherapy resistant. Active drugs led to disintegration of tumor spheres. Interestingly, some cells in the spheres were able to survive. Epirubicin and especially salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, showed high efficacy in a high proportion of cells. Furthermore, our data suggested that curcumin, a natural biologically active compound that is extracted from the plant Curcuma longais a promising agent for cancer treatment. Docetaxel, cyclophosphamide, and 5-fluoruracil showed lower cytotoxic effects onto the cells in the spheres. Conclusions: Our results show, for the first time, that stem cells circulating in peripheral blood, capable of forming spheroids are way more resistant to anticancer drugs than the remnant circulating tumor cells. We, furthermore, demonstrate that salinomycin and curcumin efficiently destroy spheroids cultured from CETCs, strengthening their role as promising anticancer therapeutics.

scholarly journals Spectroscopic Elucidation of Some Complexes of Vanillin Semicarbazone

2021 ◽  
Vol 37 (4) ◽  
pp. 826-832
Author(s):  
Navneet Sinha ◽  
Rajnish Kumar ◽  
Vijay Pratap Singh ◽  
Deepak KUMAR ◽  
Shivadhar Sharma
Keyword(s):  
Schiff Base ◽  
Biological Activities ◽  
Free Ligand ◽  
Esr Spectra ◽  
Biologically Active ◽  
Distortion Parameter ◽  
Axial Ligands ◽  
Distorted Octahedral ◽  
Semicarbazide Hydrochloride ◽  
Uv Visible

3-Phenyl-4-methoxybenzaldehyde undergoes condensation with semicarbazide hydrochloride to form a Schiff-base i.e. 3-phenyl-4-methoxybenzaldehyde semicarbazone (abbreviated as MBS). It undergoes complexation with Vanadium(II), Manganese(II), and Copper(II). The comparison of FTIR-spectra of complexes with that of free ligand helps ascertain the coordination points of ligand through the nitrogen of –CH=N– group and oxygen of group. The axial ligands have been varied by chloride, acetate and nitrate ions. The UV/Visible and ESR spectra of complexes predicts their tetragonally distorted octahedral (D4h) symmetry. The tetragonal distortion parameter (Dt) is observed maximum for chloride while it is minimum for nitrate along z-axis. Both vanillin and semicarbazide are established biologically active compounds and hence their biological activities may be enhanced by their complexation and than a versatile field may be developed for further exploration.

scholarly journals The relationship of obesity and prostate cancer (review)

2020 ◽  
Vol 17 (2) ◽  
pp. 147-155
Author(s):  
Maxim N. Peshkov ◽  
Galina P. Peshkova ◽  
Igor V. Reshetov
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Tumor Cells ◽  
Tumor Development ◽  
Biologically Active ◽  
Igf Binding Proteins ◽  
Cancer Review ◽  
Igf Binding

Obesity is a critical risk factor for prostate cancer (PCa). Adipose tissue plays an important role in tumor development, including growth, invasion, and metastasis. Diet and dietary components affect the progression of prostate cancer; however, the mechanisms underlying these associations remain unclear. Extraprostatic prostate tumor cells form a new microenvironment in the periprostatic adipose tissue, which alters these interactions and promotes tumor progression. Hyperinsulinemia leads to an increase in the level of free or biologically active insulin-like growth factor (IGF-1) due to a decrease in the production of IGF-binding proteins. Hypoandrogenism promotes the development of a more aggressive type of prostate cancer (higher Gleason scores). Adipokines of adipose tissue and cytokines (for example, interleukin-6 (IL-6) and tumor necrosis factor (TNF-), angiogenic factors (for example, vascular endothelial growth factor (VEGF), apelin (AGTRL1) and other factors (for example, leptin and adiponectin) have multiple effects on prostate cancer cells. Tumor cells interact directly or indirectly with adipocytes. Yellow (inactive) bone marrow is adipose tissue with separate islands of reticular tissue. It is located in the medullary canals of the tubular bones and in parts of the cells of the cancellous bone. Bone tissue is the object of the most frequent metastasis in prostate cancer, and with age, the content of fat cells in it increases. Bone marrow adipose tissue interacts with tumor cells, osteoblasts and other stromal cells and participates in the organization of the tumor microenvironment. Adipokines are key molecules in the interaction between tumor cells and adipose tissue, which is carried out through various mechanisms. A better understanding of the role of adipose tissue in the induction and progression of prostate cancer will lead to effective therapeutic strategies for this disease.

scholarly journals Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics

2021 ◽  
Vol 22 (23) ◽  
pp. 13044
Author(s):  
Ari Meerson ◽  
Soliman Khatib ◽  
Jamal Mahajna
Keyword(s):  
Stem Cells ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Cancer Therapeutics ◽  
Chemotherapeutic Agents ◽  
Biologically Active ◽  
Approved Drugs ◽  
Multiple Signaling

Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor’s resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.

scholarly journals Effect of bioactive extracts with high cytokinin content from micelial biomass of Hericium coralloides and Fomitopsis officinalis on tumor cells in vitro

2019 ◽  
Vol 79 (3) ◽  
pp. 31-37
Author(s):  
N. Vedenicheva ◽  
G. Al-Maali ◽  
N. Bisko ◽  
I. Kosakivska ◽  
L. Garmanchuk ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Tumor Cells ◽  
Wide Spectrum ◽  
Zeatin Riboside ◽  
Biologically Active ◽  
Therapeutic Effects ◽  
Mycelial Biomass ◽  
Medicinal Mushrooms ◽  
Methanolic Extracts

Phytohormones cytokinins are known to promote cell division in plants. Contrary, in animal's and human's tissues they induce apoptosis and block the cell cycle of a wide spectrum of tumour cells. Therapeutic effects of cytokinins, specifically their anticancer and immunomodulatory actions are similar to those of medicinal mushrooms. We detected cytokinins in mycelial biomass of two species of medicinal mushrooms growing in vitro (Fomitopsis officinalis strain 5004 and Hericium coralloides strain 2332) using HPLC-MS. Trans-zeatin, zeatin riboside, zeatin-O-glucoside and isopentenyladenine were found. Crude extracts and purified cytokinin fractions from mycelial biomass were tested on the growth and development of cultures of tumor cells lines: Hela (MTT-assay), T24/83 (viability and level apoptotic cells) and HepG2 (consumption of glucose). The effect of cytokinin fraction from mycelial biomass of Fomitopsis officinalis on pathogenic cells was higher compared to Hericium coralloides one. The data obtained revealed a higher cytotoxic/cytostatic effect of the purified cytokinin fractions in comparison with crude methanolic extracts; also higher apoptotic index was found. Under the influence of the test agents the intensification of glucose uptake into cells was observed. This indicator was higher for crude mushroom mycelium extracts, whereas under the action of purified fractions the glucose uptake rate was lower, thus decreased glycolysis level was recorded. Also, the effect of both crude extract and purified fraction from H. coralloides mycelial biomass on glucose uptake in the conditioned medium was lower against F. officinalis.These results confirm the assumption that biologically active substances of medicinal mushrooms with high pharmacological potential include cytokinins.

scholarly journals Phospholipid Metabolism Is Associated with HIV Rebound Upon Treatment Interruption

2020 ◽  
Author(s):  
Leila B. Giron ◽  
Emmanouil Papasavvas ◽  
Xiangfan Yin ◽  
Aaron R. Goldman ◽  
Hsin-Yao Tang ◽  
...  
Keyword(s):  
Viral Load ◽  
Antiretroviral Therapy ◽  
Tumor Cells ◽  
Treatment Interruption ◽  
Phospholipid Metabolism ◽  
Biologically Active ◽  
Inflammatory Factors ◽  
Hiv Latency ◽  
Potential Contribution ◽  
Viral Rebound

ABSTRACTLipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from the plasma of 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load setpoints post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the pro-inflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral setpoints upon ART cessation. Furthermore, higher pre-ATI levels of the pro-inflammatory byproduct of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible pro-inflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during- and post-ART warrants further investigation.IMPORTANCEThe likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a function of the interplay between the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that modulate these reservoirs. There is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the pro-inflammatory lysophosphatidylcholine and its intestinal metabolic byproduct, trimethylamine-N-oxide, and both faster time-to-viral rebound and higher viral load setpoint post ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during- and post-ART.

scholarly journals Milk-derived exosomes (MDEs) have a different biological effect on normal fetal colon epithelial cells compared to colon tumor cells in a miRNA-dependent manner

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Shimon Reif ◽  
Yaffa Elbaum Shiff ◽  
Regina Golan-Gerstl
Keyword(s):  
Epithelial Cells ◽  
Protein Expression ◽  
Human Milk ◽  
Tumor Cells ◽  
Expression Profiles ◽  
Biological Effects ◽  
Biologically Active ◽  
Type I ◽  
Dependent Manner ◽  
Mesenchymal Transformation

Abstract Background Breastfeeding is the ideal source of infant nutrition. Human milk consists not only of nutrients but also biologically active components. Among these latter compounds, exosomes contain proteins, lipids, mRNAs and miRNAs. Methods To elucidate the biological effects of milk-derived exosomes (MDEs) on normal colonic epithelial cells compared to colonic tumor cells, we incubated cells with MDEs. MDEs were able to enter into normal and tumor cells and change their miRNA expression profiles. Proliferation, cell morphology and protein expression were analyzed in these cells. Results Human milk-derived exosomes induced proliferation- and epithelial mesenchymal transformation-related changes, such as collagen type I and twist expression, in normal but not in tumor cells. PTEN, a target of miRNA-148a, was downregulated in normal but not in tumor cells following incubation with MDEs. Moreover, miRNA-148a-3p knockdown cells were used to demonstrate the importance of miRNA in the effect of exosomes on cell proliferation and protein expression. MDEs inhibited proliferation and DNMT1 expression in cells with knockdown of miRNA-148a. Conclusions In conclusion, the positive effect of exosomes on normal cells without affecting tumor cells may presents an aspect of their safety when considering it use as a nutritional supplement to infant formula.

682 Antibody-mediated blockade of interleukin-10 receptor-alpha promotes the activation of immune cells from in vitro dissociated tumor samples

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A721-A721
Author(s):  
Alexey Berezhnoy ◽  
Kalpana Shah ◽  
Daorong Liu ◽  
Peter Lung ◽  
Vatana Long ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Interferon Gamma ◽  
Expression Profiles ◽  
Interleukin 10 ◽  
Biologically Active ◽  
List Type ◽  
Receptor Alpha

BackgroundInterleukin-10 (IL-10) is a multifunctional cytokine that can mediate immune suppression or activation depending on the immunological context. Mouse studies have demonstrated that blockade of IL-10 enhances immune response against tumors and chronic viral infections;1 2 intriguingly, high concentrations of long-acting, pegylated IL-10 have also shown anti-tumor activity.3 Here we investigated IL-10 and IL-10 receptor-alpha (IL-10RA) expression profiles in normal and tumor tissues as well as the immunological effects of modulating the IL-10 pathway via antibody-mediated blockade of IL-10RA.MethodsIL-10 and IL-10RA mRNA are expressed by several tumors, including renal, lung, breast, and colon cancers. Fluorescent in-situ hybridization revealed that the majority of IL-10RA was expressed by CD3-negative tumor-infiltrating cells, localized in close proximity to T cells in the tumor microenvironment (TME). Immunohistochemistry studies confirmed expression of IL-10RA in the TME, while no expression was detected in healthy tissues. Furthermore, dissociated tumor cells produced biologically active levels of IL-10 in culture.ResultsMonoclonal antibodies (mAbs) against IL-10RA prevented IL-10 signaling and enhanced release of IL-12 by monocyte-derived dendritic cells activated with suboptimal LPS concentrations. The effect of IL-10RA blockade was greater than that observed with IL-10 neutralizing mAbs. In mixed lymphocyte reactions and superantigen-driven T-cell activation, IL-10RA blockade enhanced IL-2 secretion by T lymphocytes. Consistent with earlier observations in mouse models,4 the effect of IL-10RA blockade was nonredundant with blockade of the PD-1/PD-L1 axis, resulting in enhanced IL-2 and interferon-gamma secretion by T cells when both pathways were inhibited. Blockade of IL-10RA during CD3-redirected in vitro killing of tumor cells by PBMC induced IL-12 release as well as upregulation of CD86 and HLA-DR by CD3-negative cells. In in vitro dissociated tumor cells, IL-10RA blockade induced release of IL-2, interferon-gamma and other proinflammatory cytokines; additional PD-1/PD-L1 axis blockade further enhanced cytokine release.ConclusionsIn summary, antibody-mediated IL-10RA blockade can potentiate immune activation in the dissociated tumor cells and may be a valuable addition to cancer immunotherapies, including redirected T-cell killing and checkpoint blockade.ReferencesVicari A, et al. J. Exp. Med 2002;196:541–549.Ejrnaes M, et al. J Exp Med 2006;203:2461–72.Emmerich J, et al. Cancer Res 2012. 72:3570–3581.Brooks D, et al. Proc Natl Acad Sci U S A 2008;105:20428–33.

Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT

2021 ◽  
Author(s):  
Yihui Zhu ◽  
Zhonghua Tao ◽  
Ying Chen ◽  
Shuchen Lin ◽  
Mingyu Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Distant Metastasis ◽  
Intercellular Communication ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Biologically Active ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Purpose Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high risk of distant metastasis, in which the intercellular communication between tumor cells also plays a role. Exosomes can be released by tumor cells and promote distant metastasis through intercellular communication or changes in tumor microenvironment, it is an optimized transportation facility for biologically active payloads. This was a hypothesis-generating research on role of exosomal payload in TNBC distant metastasis. Methods Exosomes isolated from supernatant of MDA-MB-231 and MDA-MB-231-HM (a highly pulmonary metastatic variant of parental MDA-MB-231 cells) were characterized. Transwell assay, wound healing and CCK-8 assay were employed to explore the effect of exosomal MMP-1 on the metastatic capability of TNBC cells in vitro. Human breast cancer lung metastasis model in nude mice was established to observe the effect of exosomal MMP-1 in vivo. Tissue microarray and blood samples of TNBC patients were applied to analyze the relevance between MMP-1 with metastasis. Results MDA-MB-231-HM cells secrete exosomes enriched MMP-1, which can be taken up and enhance invasion and migration activities of TNBC cells. After ingesting exosomes enriched with MMP-1, cells secrete more MMP-1, which may interact with membrane G protein receptor protease activated receptor 1 (PAR1), thereby initiating epithelial-mesenchymal transition (EMT) to enhance capability of migration and invasion. The expressions of MMP-1 and PAR1 in the metastases of the 231-HM-exo treated mice were both up-regulated. Clinically, the exosomal MMP-1 can be detected from serum of patients with metastasis at higher concentration than that in pre-operative patients. Moreover, in patients with multiple distant metastases, the level of exosomal MMP-1 is also higher than that in patients with single lesion. Conclusion MMP-1 from TNBC cells of high metastasis potential can promote the distant metastasis of transform those with low metastasis potential through PAR1-mediated EMT and is likely to be a potential molecular marker.

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