New Oxidovanadium(IV) Coordination Complex Containing 2-Methylnitrilotriacetate Ligands Induces Cell Cycle Arrest and Autophagy in Human Pancreatic Ductal Adenocarcinoma Cell Lines

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.

Molecular and Cellular Mechanisms of Cytotoxic Activity of Vanadium Compounds against Cancer Cells

“…These studies highlight the importance of the chemical form of vanadium-based complexes in determining their mechanism of action. In our team study, the oxidovanadium complex containing quinolinium cation (66) induced cycle arrest in the G2/M phase with simultaneous triggering of the p53/p21 pathway in pancreatic cancer cell lines [79]. Induction of the p53/p21 pathway was also determined in cervical cancer cells treated by vanadium complexes of nicotinoyl hydrazine (67 and 68) [80].…”

“…Furthermore, we have determined that vanadium complexes with phenanthroline (45,47) also trigger the necroptosis pathway in a human pancreatic ductal adenocarcinoma cell line [52]. In another study, we have found that an oxidovanadium complex with quinolinium cation (66) induced autophagic process in pancreatic cancer cells with simultaneous increase in the RAGE protein level [79]. Autophagy was also detected in vanadium-treated (90) breast cancer cells [101].…”

The Role of Autophagy in Pancreatic Cancer—Recent Advances

“…In addition to the possibilities inherent in combination therapy, pre-clinical studies continue to provide us with new chemical moieties which are potentially promising in PDAC therapy. These include metal moeities such as oxidovanadium (IV) coordination complexes which have been shown to be toxic to PDAC cell lines, but not non-tumor human immortalized pancreas duct epithelial cells [55]. Interestingly, these compounds induce, rather than inhibit autophagy, so their anti-proliferative activity may be exerted via other mechanisms, such as increased reactive oxygen species generation [55].…”

Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends

“…In addition, they hypothesized (on the basis of studies conducted by other researchers) that the VOL(bipy) complex may be modified by coapplication with an antioxidant to be safer than the administration thereof alone. In turn, a study reported by Kowalski et al [164] revealed that oxidovanadium(IV) coordination complexes containing a 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer. As suggested, the molecular mechanisms of cytotoxicity of these complexes were dependent on generation of ROS and cell cycle arrest in the G2/M phase with simultaneous activation of the p53/p21 pathway.…”