Refine
Document Type
- Article (11)
Language
- English (11)
Has Fulltext
- yes (11)
Is part of the Bibliography
- no (11)
Keywords
- - (8)
- X-ray analysis (2)
- cytotoxicity (2)
- in vitro cytotoxic activity (2)
- mTHPC (2)
- photodynamic therapy (2)
- reactive oxygen species (2)
- 1,2,3-benzotriazoles (1)
- 1,2,4-triazoles (1)
- 1,3,5-triazines (1)
- 2 (1)
- 2,4-diamino-1,3,5-triazines (1)
- 2-imino-2 (1)
- 2-imino-2<i>H</i>-chromen-3-yl-1,3,5-triazines (1)
- 2-imino-coumarins (1)
- 2-iminocoumarins (1)
- 2<i>H</i>-chromen-3-yl-1,3,5-triazines (1)
- 5637 (1)
- <i>Lannea barteri</i> (1)
- <i>N</i>-acylhydrazones (1)
- <i>N</i>-sulfonylhydrazones (1)
- DNA damage (1)
- Ethiopia (1)
- GPx1 knockout (1)
- HepG2 (1)
- KYSE 70 (1)
- Pt(II) complexes (1)
- SiSo (1)
- adherent human carcinoma cell lines (1)
- amides (1)
- anticancer drugs (1)
- apoptosis (1)
- autophagy (1)
- benzothiazoles (1)
- benzoxazoles (1)
- cancer (1)
- cancer cells (1)
- cancer therapy (1)
- carboplatin (1)
- cell cycle (1)
- cisplatin (1)
- combination assay (1)
- copper(II) complexes (1)
- coumarins (1)
- extractions (1)
- glutathione peroxidase (1)
- glutathione peroxidase-1 (1)
- hybrid molecules (1)
- hydrazones (1)
- imidazo[2,1-<i>c</i>][1,2,4]triazol-3(5<i>H</i>)-imines (1)
- in vitro anticancer activity (1)
- in vitro antitumor activity (1)
- leaf (1)
- medicinal plants (1)
- necrosis (1)
- oxaliplatin (1)
- oxidative stress (1)
- pentathiepin (1)
- quinolines (1)
- stem bark (1)
- structure (1)
- sulfonamides (1)
- sulfur (1)
- synergism (1)
- synthesis (1)
- thioureas (1)
- ureas (1)
Institute
Publisher
- MDPI (11) (remove)
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.
A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC50 values ranging from 0.04 μM to 15.66 μM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7′ of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7′ of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.
The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin
(1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens.
Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment
strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT),
where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive
oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is
5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment
of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT
and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different
tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity
were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the
combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also
observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels
were observed after combination but apoptosis induction was not necessarily increased compared
to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic
subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion,
pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards
Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.
The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosisand the development of anticancer drug resistance has been extensively and controversially discussed.The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity.For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generatedand compared to the native cell line with regards to morphology, growth and metabolic rates,and oxidative stress defenses. Furthermore, the IC50values of two peroxides and 16 widely usedanticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increasesin the cytotoxic potency of hydrogen peroxide andtert-butylhydroperoxide, the anticancer drugscisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found.While a concentration dependent increases in intracellular reactive oxygen species (ROS) levelswere observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide,no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the nativecell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decreasein glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting thatfactors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in theGPx1 knockout cells.