Azulene hydrazide-hydrazones for selective targeting of pancreatic cancer cells
Language English Country France Media print-electronic
Document type Journal Article
PubMed
36156366
DOI
10.1016/j.biopha.2022.113736
PII: S0753-3322(22)01125-8
Knihovny.cz E-resources
- Keywords
- Cancer, Chelators, HIF-1α, Hydrazone, NDRG1, TfR1,
- MeSH
- Azulenes MeSH
- Iron Chelating Agents pharmacology MeSH
- Hydrazines MeSH
- Hydrazones pharmacology MeSH
- Hydroxamic Acids MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Pancreatic Neoplasms * drug therapy MeSH
- Receptors, Transferrin MeSH
- Thiosemicarbazones * pharmacology MeSH
- Iron MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- azulene MeSH Browser
- Azulenes MeSH
- Iron Chelating Agents MeSH
- Hydrazines MeSH
- Hydrazones MeSH
- Hydroxamic Acids MeSH
- Receptors, Transferrin MeSH
- Thiosemicarbazones * MeSH
- Iron MeSH
Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.
BIOCEV 1st Faculty of Medicine Charles University Prague Průmyslová 595 252 50 Vestec Czech Republic
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