New oxidovanadium(IV) coordination complex containing 2-methylnitrilotriacetate ligands induces cell cycle arrest and autophagy in human pancreatic ductal adenocarcinoma cell lines

Szymon Kowalski , Dariusz Wyrzykowski , Stanisław Hac , Michał Rychłowski , Marek Witold Radomski , Iwona Inkielewicz-Stepniak

Abstract

Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3−), N-(2-carbamoylethyl)iminodiacetate (ceida3−) and N-(phosphonomethyl)-iminodiacetate (pmida4−) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy. The results showed that these oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2), but not on non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE) over the concentration range of 10–25 μM, following 48 h incubation. Furthermore, molecular mechanisms of cytotoxicity of [4-NH2-2-Me(Q)H][VO(bcma)(H2O)]2H2O (T1) were dependent on antiproliterative activity, increased ROS generation, cell cycle arrest in G2/M phase with simultaneous triggering of the p53/p21 pathway, binucleation, and induction of autophagy. Our study indicates that oxidovanadium(IV) coordination complexes containing 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer.
Author Szymon Kowalski
Szymon Kowalski,,
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, Dariusz Wyrzykowski (FCh / DGICh / PBChN)
Dariusz Wyrzykowski,,
- Pracownia Biologicznej Chemii Nieorganicznej
, Stanisław Hac
Stanisław Hac,,
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, Michał Rychłowski (IFB / IB / LVMB)
Michał Rychłowski,,
- Laboratory of Virus Molecular Biology
, Marek Witold Radomski
Marek Witold Radomski,,
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, Iwona Inkielewicz-Stepniak
Iwona Inkielewicz-Stepniak,,
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Journal seriesInternational Journal of Molecular Sciences, ISSN 1422-0067, (N/A 100 pkt)
Issue year2019
Vol20
No2
Pages1-20
Publication size in sheets0.95
Article number261
Keywords in Englishvanadium complex, pancreatic cancer, autophagy, mitotic catastrophe, cell cycle arrest
ASJC Classification1604 Inorganic Chemistry; 1605 Organic Chemistry; 1606 Physical and Theoretical Chemistry; 1706 Computer Science Applications; 1607 Spectroscopy; 1312 Molecular Biology; 2700 General Medicine; 1503 Catalysis
DOIDOI:10.3390/ijms20020261
URL https://doi.org/10.3390/ijms20020261
Languageen angielski
LicenseJournal (articles only); published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)100
ScoreMinisterial score = 100.0, 30-09-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.147; WoS Impact Factor: 2017 = 3.687 (2) - 2017=3.878 (5)
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