The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo

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.

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In vivo-in vitro correlation of antitumor activity of heat shock protein 90 (HSP90) inhibitors with a pharmacokinetics/pharmacodynamics analysis using NCI-N87 xenograft mice

Xenobiotica ◽

10.1080/00498254.2021.1942588 ◽

2021 ◽

pp. 1-30

Author(s):

Noriaki Ohminato ◽

Miho Nagayasu ◽

Kazuhisa Ozeki ◽

Ryoichi Saitoh ◽

Naomi Ono ◽

...

Keyword(s):

Heat Shock ◽

Antitumor Activity ◽

Heat Shock Protein ◽

Heat Shock Protein 90 ◽

Hsp90 Inhibitors ◽

Xenograft Mice

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Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

Molecular Biology Reports ◽

10.1007/s11033-021-06336-7 ◽

2021 ◽

Author(s):

Naresh Damuka ◽

Miranda Orr ◽

Paul W. Czoty ◽

Jeffrey L. Weiner ◽

Thomas J. Martin ◽

...

Keyword(s):

Mechanism Of Action ◽

Ex Vivo ◽

Neuroblastoma Cells ◽

Proper Function ◽

Brain Functions ◽

Biodistribution Studies ◽

Positron Emission ◽

Vitro Binding

AbstractMicrotubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

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Surface Labeling with Adhesion Protein FimH Improves Binding of Immunotherapeutic Agent Salmonella Ty21a to the Bladder Epithelium

Bladder Cancer ◽

10.3233/blc-200382 ◽

2020 ◽

pp. 1-12

Author(s):

Maroeska J. Burggraaf ◽

Lisette Waanders ◽

Mariska Verlaan ◽

Janneke Maaskant ◽

Diane Houben ◽

...

Keyword(s):

Bladder Cancer ◽

Antitumor Activity ◽

Bladder Wall ◽

Bladder Epithelium ◽

Modest Improvement ◽

Adhesion Protein ◽

Survival Experiment ◽

Muscle Invasive

BACKGROUND: Bladder cancer is the ninth most common cancer in men. 70% of these tumors are classified as non-muscle invasive bladder cancer and those patients receive 6 intravesical instillations with Mycobacterium bovis BCG after transurethral resection. However, 30% of patients show recurrences after treatment and experience severe side effects that often lead to therapy discontinuation. Recently, another vaccine strain, Salmonella enterica typhi Ty21a, demonstrated promising antitumor activity in vivo. Here we focus on increasing bacterial retention in the bladder in order to reduce the number of instillations required and improve antitumor activity. OBJECTIVE: To increase the binding of Ty21a to the bladder wall by surface labeling of the bacteria with adhesion protein FimH and to study its effect in a bladder cancer mouse model. METHODS: Binding of Ty21a with surface-labeled FimH to the bladder wall was analyzed in vitro and in vivo. The antitumor effect of a single instillation of Ty21a+FimH in treatment was determined in a survival experiment. RESULTS: FimH-labeled Ty21a showed significant (p < 0.0001) improved binding to mouse and human cell lines in vitro. Furthermore, FimH labeled bacteria showed ∼5x more binding to the bladder than controls in vivo. Enhanced binding to the bladder via FimH labeling induced a modest improvement in median but not in overall mice survival. CONCLUSIONS: FimH labeling of Ty21a significantly improved binding to bladder tumor cells in vitro and the bladder wall in vivo. The improved binding leads to a modest increase in median survival in a single bladder cancer mouse study.

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Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽

10.3390/molecules26071838 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1838

Author(s):

Naglaa M. Ahmed ◽

Mahmoud M. Youns ◽

Moustafa K. Soltan ◽

Ahmed M. Said

Keyword(s):

Molecular Modeling ◽

Antitumor Activity ◽

Cell Lines ◽

Cancer Cell ◽

Antiproliferative Activity ◽

Antitumor Agents ◽

Cancer Cell Lines ◽

Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

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A Novel Fully Human Agonistic Single Chain Fragment Variable Antibody Targeting Death Receptor 5 with Potent Antitumor Activity In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms18102064 ◽

2017 ◽

Vol 18 (10) ◽

pp. 2064 ◽

Cited By ~ 3

Author(s):

Gaoxin Lei ◽

Menglong Xu ◽

Zhipan Xu ◽

Lili Gu ◽

Chenchen Lu ◽

...

Keyword(s):

Antitumor Activity ◽

Death Receptor ◽

Death Receptor 5 ◽

Single Chain ◽

Chain Fragment ◽

Single Chain Fragment Variable ◽

Antibody Targeting ◽

Single Chain Fragment

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Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan

Microbiology ◽

10.1099/mic.0.079111-0 ◽

2014 ◽

Vol 160 (10) ◽

pp. 2157-2169 ◽

Cited By ~ 13

Author(s):

Sudarson Sundarrajan ◽

Junjappa Raghupatil ◽

Aradhana Vipra ◽

Nagalakshmi Narasimhaswamy ◽

Sanjeev Saravanan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Mechanism Of Action ◽

Catalytic Domain ◽

Antibiotic Sensitivity ◽

High Sensitivity ◽

Common Mechanism ◽

Cross Bridge ◽

Sensitivity Pattern

P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.

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