Abstract
Simple SummaryBleomycin (BLM) is a medication introduced used to treat various types of cancer, including testicular cancer, ovarian cancer, and Hodgkin’s disease. Its most serious side effect is pulmonary fibrosis and impaired lung function. Using A549 human lung cells it is shown that, in parallel to an increased cell toxicity and DNA damage, BLM causes a marked enlargement of the cell nucleus. This effect is abolished by inorganic polyphosphate (polyP), if this physiological polymer is administered together with BLM. The detoxification of BLM is–most likely–caused by the upregulation of the gene encoding the BLM hydrolase which inactivates BLM in vitro and in vivo. This study contributes also to a rational application in COVID-19 patients since polyP prevents binding of SARS-CoV-2 to host cells.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.
Highlights
The bleomycins (BLMs) are glycopeptides with antineoplastic activity, which bind to DNA in a particular manner and cause strand-scissions in a reaction in which Fe(II) and oxygen are required [1]
By using A549 cells, we show that the BLM-caused reduction of cell viability–most likely due to an increased DNA damaging effect and a subsequent chromatin expansion process–can be sensitively prevented by co-incubation with polyP (Figure 2)
At a concentration of around 10 to 20 μg mL−1 a maximum is achieved with about 60% reduction of the proliferation rate
Summary
The bleomycins (BLMs) are glycopeptides (size of ~1415 g/mol) with antineoplastic activity, which bind to DNA in a particular manner and cause strand-scissions in a reaction in which Fe(II) and oxygen are required [1]. It was the group of Umezama and colleagues [2] who first discovered these metallo-glycopeptide antibiotics in Streptomyces verticillis, purified them and determined their structures. The compound can be dissected into several regions; the metal binding region, the linker with its small polyketide stretch, the DNA binding site and the disaccharide position [8] (Figure 1). Among a series of transition metal ions that bind to the nitrogen atoms of BLM, like Fe, Co, Cu, etc., the divalent Fe(II) cation is the most important one for causing biological activity [10]
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