scholarly journals Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

2021 ◽  
Author(s):  
Alexander M.A. van der Wiel ◽  
Victoria Jackson-Patel ◽  
Raymon Niemans ◽  
Ala Yaromina ◽  
Emily Liu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Hypoxia ◽  
Human Tumor ◽  
Tumor Oxygenation ◽  
Antitumor Effects ◽  
Wide Range ◽  
Hypoxic Tumor

Abstract Background Hypoxia-activated prodrugs (HAPs) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. The present study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacological properties. Methods Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods. In vitro, 2D monolayer and 3D spheroid and multicellular layer cultures were used to investigate the hypoxia-selectivity of CP-506. In vivo, the causal relationship between tumor oxygenation and antitumor effects of CP-506 was assessed. Mice bearing a range of human tumor xenografts were exposed to CP-506 and tumor growth was monitored. A multivariate linear regression model was used to identify factors associated with CP-506 treatment outcome. Results Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µM (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. Two well-oxygenated models were refractory to treatment despite intrinsic anoxic sensitivity in vitro. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 to significantly correlate with treatment response. Conclusions Our results demonstrate that CP-506 selectively sterilizes hypoxic tumor cells and has broad antitumor activity. Our data also indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3132-3137 ◽  
Author(s):  
Crystal Y. Koh ◽  
Bruce R. Blazar ◽  
Thaddeus George ◽  
Lisbeth A. Welniak ◽  
Christian M. Capitini ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Antitumor Effects

Abstract Subsets of natural killer (NK) cells are characterized by the expression of inhibitory and/or stimulatory receptors specific for major histocompatibility complex (MHC) class I determinants. In mice, these include the Ly49 family of molecules. One mechanism by which tumor cells may evade NK cell killing is by expressing the appropriate MHC class I and binding inhibitory Ly49 receptors. Therefore, the question of whether blocking the interaction between the Ly49 inhibitory receptors on NK and MHC class I cells on tumor cells augments antitumor activity was investigated. Blockade of Ly49C and I inhibitory receptors using F(ab′)2 fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro. The effect of 5E6 F(ab′)2 was specific for the MHC of the tumor, as the use of F(ab′)2 of the mAb against Ly49G2 failed to increase NK activity. Treatment of leukemia-bearing mice with 5E6 F(ab′)2 fragments or adoptive transfer of NK cells treated ex vivo with the F(ab′)2 resulted in significant increases in survival. These results demonstrate that blockade of NK inhibitory receptors enhances antitumor activity both in vitro and in vivo, suggesting that NK inhibitory receptors can be responsible for diminishing antitumor responses. Therefore, strategies to block inhibitory receptors may be of potential use in increasing the efficacy of immunotherapy.

scholarly journals MLN8054, an Inhibitor of Aurora A Kinase, Induces Senescence in Human Tumor Cells Both In vitro and In vivo

2010 ◽  
Vol 8 (3) ◽  
pp. 373-384 ◽  
Author(s):  
Jessica J. Huck ◽  
Mengkun Zhang ◽  
Alice McDonald ◽  
Doug Bowman ◽  
Kara M. Hoar ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Human Tumor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Human Tumor Cells

scholarly journals Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Simeng Wang ◽  
Xinrui Zhou ◽  
Zekun Zeng ◽  
Mengjun Sui ◽  
Lihong Chen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Disulfide Bonds ◽  
Tumor Targeting ◽  
Tumor Hypoxia ◽  
Animal Experiments ◽  
Complex Iii ◽  
Mitochondrial Activity ◽  
Hypoxic Tumor

Abstract Background Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. Methods We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. Results Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. Conclusions Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment. Graphic abstract

scholarly journals Hydroxychloroquine Synergizes With The PI3K Inhibitor BKM120 to Exhibit Antitumor Efficacy Independent of Autophagy

2021 ◽  
Author(s):  
Xin Peng ◽  
Shaolu Zhang ◽  
Wenhui Jiao ◽  
Zhenxing Zhong ◽  
Yuqi Yang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Single Agent ◽  
Antitumor Efficacy ◽  
Antitumor Effects ◽  
Autophagy Inhibitor

Abstract Background: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.Methods: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

1984 ◽  
Vol 2 (4) ◽  
pp. 282-286 ◽  
Author(s):  
S E Salmon ◽  
L Young ◽  
B Soehnlen ◽  
R Liu
Keyword(s):  
Antitumor Activity ◽  
Clonogenic Assay ◽  
Human Tumor ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
Early Results ◽  
Colony Forming Units ◽  
Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

scholarly journals Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 29 ◽  
Author(s):  
Daiana K. Frade Silva ◽  
Sâmia S. Duarte ◽  
Thaís M. H. Lisboa ◽  
Rafael C. Ferreira ◽  
Ana Luíza de O. Lopes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Antitumor Effect ◽  
Inflammatory Responses ◽  
Lethal Dose ◽  
Ehrlich Ascites Carcinoma ◽  
Antitumor Effects ◽  
Th2 Immune Response

Tumor cells have specific features, including angiogenesis induction, cell cycle dysregulation, and immune destruction evasion. By inducing a T helper type 2 (Th2) immune response, tumor cells may favor immune tolerance within the tumor, which allows progression of cancer growth. Drugs with potential antitumor activity are the spiro-acridines, which is a promising new class of acridine compounds. Herein, the novel spiro-acridine (E)-5′-oxo-1′-((3,4,5-trimethoxybenzylidene)amino)-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-17) was synthesized and tested for antitumor effects. Toxicity evaluation was performed in mice after acute treatment (2000 mg/kg, intraperitoneally, i.p.). The Ehrlich ascites carcinoma model was used to investigate the antitumor activity of AMTAC-17 (12.5, 25, or 50 mg/kg, i.p.) after seven days of treatment. Effects on the cell cycle, angiogenesis, and inflammatory responses were investigated. LD50 (lethal dose 50%) was estimated to be higher than 5000 mg/kg. AMTAC-17 reduced the Ehrlich tumor’s total viable cancer cells count and peritumoral micro-vessels density, and induced an increase in the sub-G1 peak. Additionally, there was an increase of Th1 cytokine profile levels (IL-1β, TNF-α, and IL-12). In conclusion, the spiro-acridine compound AMTAC-17 presents low toxicity, and its in vivo antitumor effect involves modulation of the immune system to a cytotoxic Th1 profile and a reduction of tumor angiogenesis.

Macrophage Antitumor Activity Induced by the Antigenic Lymphoma L5178Y/DTIC Subline

1982 ◽  
Vol 68 (5) ◽  
pp. 365-371 ◽  
Author(s):  
Ornella Marelli ◽  
Alberto Mantovani ◽  
Paola Franco ◽  
Angelo Nicotin
Keyword(s):  
Antitumor Activity ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Peritoneal Macrophages ◽  
Leukemic Cells ◽  
Target Cells ◽  
Tumor Target ◽  
Growth Inhibitory

Murine leukemic cells, after in vivo treatment with antineoplastic drugs, have been shown to express new antigenic specificities that were not detectable on parental cells and that were heritable after the withdrawal of drug treatment. A study was conducted of macrophage antitumor activity triggered by LY/DTIC cells, a subline of LY murine lymphoma, antigenically altered by the drug DTIC. In vitro non-specific inhibition of tumor cell growth was exhibited by spleen and peritoneal macrophages from mice previously challenged with viable LY/DTIC. Peritoneal macrophages from LY/DTIC immune animals showed moderate, although significant lytic activity against unrelated tumor target cells. Supernatants from mixed lymphocyte-tumor cell cultures, in which LY/DTIC immune lymphocytes and LY/DTIC tumor cells had been cultured, rendered normal macrophages non-specifically growth inhibitory for tumor cells.

scholarly journals In vitro and in vivo evaluation of antitumor activity of methanolic extract of Argyreia nervosa leaves on Ehrlich ascites carcinoma

2015 ◽  
Vol 10 (2) ◽  
pp. 399
Author(s):  
Bhawna Sharma ◽  
Isha Dhamija ◽  
Sandeep Kumar ◽  
Hema Chaudhary
Keyword(s):  
Antitumor Activity ◽  
Solid Tumor ◽  
Methanolic Extract ◽  
Ehrlich Ascites Carcinoma ◽  
Ehrlich Ascites ◽  
Wide Range ◽  
Antioxidant Parameters ◽  
Argyreia Nervosa

<p>The herb of importance like <em>Argyreia nervosa</em> has shown wide range of pharmacological activities. Its methanolic extract of <em>A. nervosa</em> has been explored against Ehrlich ascites carcinoma (EAC) induced liquid and solid tumor in mice. Liquid and solid tumors were induced by intraperitoneal and subcutaneous transplantation of EAC cells in Balb/C mice. Significant and dose dependant results are observed when the mice are sacrificed on 15<sup>th</sup> day for estimation of tumor proliferation, hematological, biochemical and hepatic antioxidant parameters. Mean survival time (days) was increased to 36.5 from 20.5 extract treated mice. The extract also showed a decrease (p&lt;0.001) in body weight and percentage reduction in tumor volume respectively when it was evaluated in solid tumor induced mice for a period of 30 days.  From the result it was concluded that the extract has as a potent antitumor activity and that is comparable to 5-fluorouracil.</p><p> </p>

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