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.
Highlights
While pancreatic cancer is a relatively rare type of cancer, it is the fourth leading cause of cancer-related death worldwide [1,2,3,4]
We evaluated the cytotoxic profile of vanadium complexes on human pancreas ductal adenocarcinoma cells and compare this profile with immortalized pancreas duct cell line
We showed that T1 increased the levels of reactive oxygen species (ROS) in pancreatic cancer cells in a concentration-dependent manner
Summary
While pancreatic cancer is a relatively rare type of cancer, it is the fourth leading cause of cancer-related death worldwide [1,2,3,4]. Metal-based anticancer agents, such as cisplatin, have been developed [15]. Metal complexes form new shapes that can more effectively explore new chemical entity (NCE) structure-activity relationship, for example, an octahedral geometry, which better fits the active site of protein kinases [16]. Functionalization of metal complexes with tailor-made ligands can improve the pharmacological profile of NCE as anticancer drugs [19]. Cisplatin was the first metal-based drug approved by the FDA for cancer treatment [21]. In particular organic derivatives, are another metal-based compounds showing anticancer potential [26]. We have demonstrated that vanadium complexes decrease viability of cancer cells and the molecular mechanism of action may be dependent on organic cations [27]. We have synthesized new oxidovanadium(IV) complexes and characterized their pharmacological profile in vitro using cancer and non-cancer human pancreatic cell lines
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