Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action.
Lisa WolffSiva Sankar Murthy BandaruElias EgerHoai-Nhi LamMartin NapierkowskiDaniel BaeckerCarola SchulzkePatrick J BednarskiPublished in: International journal of molecular sciences (2021)
Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
Keyphrases
- oxidative stress
- cell death
- cell cycle
- cell proliferation
- cell cycle arrest
- papillary thyroid
- endothelial cells
- dna damage
- endoplasmic reticulum stress
- diabetic rats
- induced apoptosis
- high resolution
- induced pluripotent stem cells
- quantum dots
- pi k akt
- mass spectrometry
- computed tomography
- circulating tumor
- signaling pathway
- hydrogen peroxide
- climate change
- pluripotent stem cells
- childhood cancer
- young adults
- magnetic resonance
- human health