scholarly journals Intratumoral Administration of Astatine-211-labeled Gold Nanoparticle for Alpha Therapy

2021 ◽  
Author(s):  
Hiroki Kato ◽  
Xuhao Huang ◽  
Yuichiro Kadonaga ◽  
Daisuke Katayama ◽  
Kazuhiro Ooe ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Antitumor Effect ◽  
High Energy ◽  
C6 Glioma ◽  
Dependent Manner ◽  
Intratumoral Administration ◽  
Pancreatic Cancers ◽  
Systemic Spread ◽  
High Cytotoxicity ◽  
Poly Ethylene

Abstract Background: 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally.Results: AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions: The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide.

scholarly journals Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hiroki Kato ◽  
Xuhao Huang ◽  
Yuichiro Kadonaga ◽  
Daisuke Katayama ◽  
Kazuhiro Ooe ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Antitumor Effect ◽  
High Energy ◽  
C6 Glioma ◽  
Dependent Manner ◽  
Intratumoral Administration ◽  
Pancreatic Cancers ◽  
Systemic Spread ◽  
High Cytotoxicity ◽  
Poly Ethylene

Abstract Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract

scholarly journals Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes

2021 ◽  
Vol 9 (9) ◽  
pp. e002954
Author(s):  
Mikako Nishida ◽  
Nahoko Yamashita ◽  
Taisaku Ogawa ◽  
Keita Koseki ◽  
Eiji Warabi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Antitumor Effect ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Glut 1 ◽  
Ifn Γ

BackgroundMetformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.MethodsMitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.ResultsMet administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.ConclusionsWe found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.

Tissue Distribution and Systemic Toxicity Evaluation of Raloxifene Targeted Polymeric Micelles of Poly (Styrene-Maleic Acid)-Poly (Amide- Ether-Ester-Imide)-Poly (Ethylene Glycol) Loaded With Docetaxel in Breast Cancer Bearing Mice

2019 ◽  
Vol 14 (3) ◽  
pp. 280-291 ◽  
Author(s):  
Jaleh Varshosaz ◽  
Farshid Hassanzadeh ◽  
Batool Hashemi-Beni ◽  
Mohsen Minaiyan ◽  
Saeedeh Enteshari
Keyword(s):  
Side Effects ◽  
Antitumor Activity ◽  
Ethylene Glycol ◽  
Tissue Distribution ◽  
Tumor Cells ◽  
Maleic Acid ◽  
Polymeric Micelles ◽  
Poly Ethylene Glycol ◽  
Poly Ethylene ◽  
Ether Ester

Background: Due to the low water solubility of Docetaxel (DTX), it is formulated with ethanol and Tween 80 with lots of side effects. For this reason, special attention has been paid to formulate it in new drug nano-carriers. Objective: The goal of this study was to evaluate the safety, antitumor activity and tissue distribution of the novel synthesized Raloxifene (RA) targeted polymeric micelles. Methods: DTX-loaded RA-targeted polymeric micelles composed of poly(styrene-maleic acid)- poly(amide-ether-ester-imide)-poly(ethylene glycol) (SMA-PAEE-PEG) were prepared and their antitumor activity was studied in MC4-L2 tumor-bearing mice compared with non-targeted micelles and free DTX. Safety of the micelles was studied by Hematoxylin and Eosin (H&E) staining of tumors and major organs of the mice. The drug accumulation in the tumor and major organs was measured by HPLC method. Results: The results showed better tumor growth inhibition and increased survival of mice treated with DTX-loaded in targeted micelles compared to the non-targeted micelles and free DTX. Histopathological studies, H&E staining of tumors and immunohistochemical examination showed the potential of DTX-loaded RA-targeted micelles to inhibit tumor cells proliferation. The higher accumulation of the DTX in the tumor tissue after injection of the micelles compared to the free DTX may indicate the higher uptake of the targeted micelles by the G-Protein-Coupled Estrogen Receptors (GPER). Conclusion: The results indicate that RA-conjugated polymeric micelles may be a strong and effective drug delivery system for DTX therapy and uptake of the drug into tumor cells, and overcome the disadvantages and side effects of conventional DTX.

scholarly journals Synthesis and Evaluation of the Antitumor Activity of Novel 1-(4-Substituted phenyl)-2-ethyl Imidazole Apoptosis Inducers In Vitro

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4293
Author(s):  
Zhen-Wang Li ◽  
Chun-Yan Zhong ◽  
Xiao-Ran Wang ◽  
Shi-Nian Li ◽  
Chun-Yuan Pan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Antiproliferative Activity ◽  
Antitumor Agent ◽  
Positive Control ◽  
Selectivity Index ◽  
Time Dependent ◽  
Potential Candidate ◽  
Dependent Manner

Novel imidazole derivatives were designed, prepared, and evaluated in vitro for antitumor activity. The majority of the tested derivatives showed improved antiproliferative activity compared to the positive control drugs 5-FU and MTX. Among them, compound 4f exhibited outstanding antiproliferative activity against three cancer cell lines and was considerably more potent than both 5-FU and MTX. In particular, the selectivity index indicated that the tolerance of normal L-02 cells to 4f was 23–46-fold higher than that of tumor cells. This selectivity was significantly higher than that exhibited by the positive control drugs. Furthermore, compound 4f induced cell apoptosis by increasing the protein expression levels of Bax and decreasing those of Bcl-2 in a time-dependent manner. Therefore, 4f could be a potential candidate for the development of a novel antitumor agent.

scholarly journals Evaluation of the antitumor effect of lectin obtained from the latex of Euphorbia tirucalli against tumor cells of Ehrlich

2014 ◽  
Vol 8 (S4) ◽  
Author(s):  
Aline Richter ◽  
Caroline Mota ◽  
Fernanda Santiago ◽  
Marcelo Barbosa
Keyword(s):  
Tumor Cells ◽  
Antitumor Effect ◽  
Euphorbia Tirucalli

scholarly journals Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 422
Author(s):  
Zhanat Koshenov ◽  
Furkan E. Oflaz ◽  
Martin Hirtl ◽  
Johannes Pilic ◽  
Olaf A. Bachkoenig ◽  
...  
Keyword(s):  
Er Stress ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Human Neuroblastoma Cell ◽  
Mitochondrial Bioenergetics ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Sigma 1 Receptor ◽  
Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

scholarly journals Antitumor Effect of Mercury-Hematoporphyrin Complex on Solid-type Ehrlich Ascites Tumor Cells

1960 ◽  
Vol 80 (9) ◽  
pp. 1291-1292
Author(s):  
Mihoko Abe ◽  
Hideo Hirokawa ◽  
Yukito Masamune ◽  
Den'ichi Mizuno
Keyword(s):  
Tumor Cells ◽  
Antitumor Effect ◽  
Ehrlich Ascites Tumor ◽  
Ehrlich Ascites Tumor Cells ◽  
Ascites Tumor ◽  
Ehrlich Ascites ◽  
Solid Type

scholarly journals In Vitro- and In Vivo-Generated Defective RNAs of Satellite Panicum Mosaic Virus Define cis-Acting RNA Elements Required for Replication and Movement

2000 ◽  
Vol 74 (5) ◽  
pp. 2247-2254 ◽  
Author(s):  
Wenping Qiu ◽  
Scholthof G. Karen-Beth
Keyword(s):  
Mosaic Virus ◽  
De Novo ◽  
Stop Codon ◽  
Dependent Manner ◽  
Defective Rnas ◽  
Systemic Spread ◽  
Rna Elements ◽  
Rna Domains ◽  
Rna Accumulation

ABSTRACT Satellite panicum mosaic virus (SPMV) depends on its helper virus, panicum mosaic virus (PMV), to provide trans-acting proteins for replication and movement. The 824-nucleotide (nt) genome of SPMV possesses an open reading frame encoding a 17.5-kDa capsid protein (CP), which is shown to be dispensable for SPMV replication. To localize cis-acting RNA elements required for replication and movement, a comprehensive set of SPMV cDNA deletion mutants was generated. The results showed that the 263-nt 3′ untranslated region (UTR) plus 73 nt upstream of the CP stop codon and the first 16 nt in the 5′ UTR are required for SPMV RNA amplification and/or systemic spread. A region from nt 17 to 67 within the 5′ UTR may have an accessory role in RNA accumulation, and a fragment bracketing nt 68 to 104 appears to be involved in the systemic movement of SPMV RNA in a host-dependent manner. Unexpectedly, defective RNAs (D-RNAs) accumulated de novo in millet plants coinfected with PMV and either of two SPMV mutants: SPMV-91, which is incapable of expressing the 17.5-kDa CP, and SPMV-GUG, which expresses low levels of the 17.5-kDa CP. The D-RNA derived from SPMV-91 was isolated from infected plants and used as a template to generate a cDNA clone. RNA transcripts derived from this 399-nt cDNA replicated and moved in millet plants coinoculated with PMV. The characterization of this D-RNA provided a biological confirmation that the critical RNA domains identified by the reverse genetic strategy are essential for SPMV replication and movement. The results additionally suggest that a potential “trigger” for spontaneous D-RNA accumulation may be associated with the absence or reduced accumulation of the 17.5-kDa SPMV CP. This represents the first report of a D-RNA associated with a satellite virus.

Synergistic Apoptotic Effect of Naringenin on enhancing the Anti-Glioma Efficacy of Temozolomide in an in vitro Experimental Model

2021 ◽  
Vol 16 (10) ◽  
pp. 43-49
Author(s):  
Precilla S. Daisy ◽  
S. Kuduvalli Shreyas ◽  
R. Sathish ◽  
T.S. Anitha
Keyword(s):  
Drug Treatment ◽  
Caspase 3 ◽  
Treatment Strategies ◽  
Glioma Cells ◽  
C6 Glioma ◽  
Mitigation Strategies ◽  
Treatment Modalities ◽  
C6 Glioma Cells ◽  
Dependent Manner

Glioma is one of the most devastating and difficult-totreat brain tumors with a very poor prognosis. Despite the current treatment modalities, the overall survival rate is only 5% contributing to a high mortality rate. Nevertheless, of emerging treatment strategies, there is still a rising need for novel mitigation strategies to counteract glioma aggressiveness. One attempt towards this long-term goal was made in this study to reveal the combined efficacy of naringenin, a bioactive flavonoid on enhancing the anti-glioma potency of temozolomide in C6 glioma cells. The cytotoxic effect of temozolomide and naringenin, both individually and in combination was assessed by employing MTT assay. The synergistic effect of the drugs temozolomide and naringenin was determined by calculating the combination index. To confirm the presence of apoptotic changes in the cells at morphological level, acridine orange/ethidium bromide staining was performed. Further, the modulatory effects of the drugs on apoptotic genes, caspase-3 and BCL-2 were evaluated using quantitative real time-PCR. Interestingly, we found that the combinatorial drug treatment was in consensus and effectively inhibited the growth of C6 glioma cells in a dose-dependent manner. Furthermore, this combinatorial drug treatment significantly up-regulated the expression of the proapoptotic gene, caspase-3 and down-regulated the anti-apoptotic gene BCL-2 suggesting a shift of equilibrium towards apoptosis. Our findings suggest that naringenin can be employed as a potent drug to enhance the anti-glioma efficacy of temozolomide and could be therapeutically exploited for the management of glioma.

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