Microbial metabolites of proanthocyanidins reduce chemical carcinogen-induced DNA damage in human lung epithelial and fetal hepatic cells in vitro

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml−1 causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold). Importantly, the BLM-caused effects on cell growth and DNA integrity are substantially suppressed by polyP. In parallel, the enlargement of the nuclei/chromatin in BLM-treated cells (diameter, 20–25 µm) is normalized to ~12 µm after co-incubation of the cells with BLM and polyP. A sequential application of the drugs (BLM for 3 days, followed by an exposure to polyP) does not cause this normalization. During co-incubation of BLM with polyP the gene for the BLM hydrolase is upregulated. It is concluded that by upregulating this enzyme polyP prevents the toxic side effects of BLM. These data might also contribute to an application of BLM in COVID-19 patients, since polyP inhibits binding of SARS-CoV-2 to cellular ACE2.

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In vitro dosimetry analyses for acrolein exposure in normal human lung epithelial cells and human lung cancer cells

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2020.103576 ◽

2020 ◽

pp. 103576

Author(s):

Rui Xiong ◽

Qiangen Wu ◽

Matthew Bryant ◽

Hans Rosenfeldt ◽

Sheila Healy ◽

...

Keyword(s):

Lung Cancer ◽

Human Lung ◽

Lung Epithelial Cells ◽

Human Lung Cancer ◽

Lung Epithelial ◽

Human Lung Cancer Cells ◽

Normal Human ◽

In Vitro Dosimetry ◽

Human Lung Epithelial Cells

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Identification of novel antiviral drug combinations in vitro and tracking their development

10.1101/2020.09.17.299933 ◽

2020 ◽

Author(s):

Aleksandr Ianevski ◽

Rouan Yao ◽

Svetlana Biza ◽

Eva Zusinaite ◽

Andres Männik ◽

...

Keyword(s):

Viral Infections ◽

Human Lung ◽

Antiviral Drug ◽

A549 Cells ◽

Drug Combinations ◽

Investigational Drug ◽

Synergistic Activity ◽

Lung Epithelial ◽

Reduced Toxicity

AbstractCombination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

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