Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process

Abstract

The pancreatic cancer is the fourth leading cause of cancer-related death and characterized by one of the lowest five-year survival rate. The current therapeutic options are demonstrating minimal effectiveness, therefore studies on new potential anticancer compounds, with non-significant side effects are highly desirable. Recently, it was demonstrated that vanadium compounds, in particular organic derivatives, exhibit anticancer properties against different type of tumor as well as favorable biodistribution from a pancreatic cancer treatment perspective.In this research, we showed selective cytotoxic effect of vanadium complexes, containing phenanthroline and quinoline as an organic ligands, against human pancreatic ductal adenocarcinoma cell line (PANC-1), compared to non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE). Results exhibited that vanadium complexes inhibited autophagy process in selective cytotoxic concentration as well as caused the cell cycle arrest in G2/M phase associated with mitotic catastrophe and increased level of reactive oxygen species (ROS). Moreover, in higher concentration, vanadium derivatives induced a mix type of cell death in PANC-1 cells, including apoptotic and necroptotic process.Our investigation emphasizes the anticancer potential of vanadium complexes by indicating their selective cytotoxic activity, through different process posed by alternative type of cell deaths to apoptosis-resistant cancer cells. Further studies supporting the therapeutic potential of vanadium in pancreatic cancer treatment is highly recommended.

Vanadium compounds and cellular death mechanisms in the A549 cell line: The relevance of the compound valence

“…Our results suggest that VOSO 4 and NaVO 3 cytotoxicity in A549 cells is probably mediated by a mechanism similar to that observed in pancreatic ductal adenocarcinoma cells that consist of a mixture of alternative type of cell deaths such as apoptosis, necroptosis and mitotic catastrophe processes (Kowalski et al, ). Nevertheless, it has been clearly established that necroptosis is a TNFα‐dependent pathway (Degterev et al, ) only in situations where caspases are inhibited (Kang, Jeong, Yang, Kovalenko, & Wallach, ; Vercammen, Vandenabeele, Beyaert, Declercq, & Fiers, ); our results showed that all evaluated caspases were inhibited.…”

“…Vanadium is a transition metal that can be found in both cationic and anionic forms with six oxidation states (Deo et al, ). Most significantly, several of these vanadium compounds prevent and inhibit the growth of various types of cancer in multiple in vitro and in vivo assays (Kowalski et al, ; Leon et al, ; Rozzo et al, ). VOSO 4 and NaVO 3 have been shown to inhibit rhabdomyosarcoma cell growth at similar concentrations that the ones we used (Dabros et al, ).…”

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications

“…The ammonium monovanadate is able to induce apoptosis in both rats with breast cancer 7,12-dimethylbenz(a) anthracene induced and MCF-7 cells culture, accompanied by a strong expression of p53 [197]. Recently O) were reported to induce apoptosis of human pancreatic ductal adenocarcinoma through a mechanism that involves ROS increase [198].…”

“…Another important mechanism, of some vanadium compounds to also exhibit antiproliferative and cytotoxic effects, might be through interactions with DNA [24,179,225,226] either by interacting with DNA's nucleotide phosphate groups as propose in the case of vanadocene complexes [183,227] or through the direct intercalation with DNA such as vanadium complex of 4-pyridinecarboxylic acid, 2-[(2-hydroxy)-1-naphthalenylene] hydrazide and 1,10phenanthroline (VO-(Pahn)phen), resulting in increased ROS and oxidative DNA damage [191,198,228]. Some vanadecene complexes with non-essential amino acids have been reported in the literature [183,229], such as proline and glycine; however, it is unknown whether this class of complexes produces antitumor effects or whether it is capable of interacting with the genetic material.…”

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

“…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. An earlier study conducted by the same author [165] showed a selective cytotoxic effect of V complexes containing phenanthroline and quinoline as organic ligands against a human pancreatic ductal adenocarcinoma cell line (PANC-1). The results from this work revealed that V complexes caused cell cycle arrest in the G2/M phase and induced a significant increase in ROS generation in a time-and concentration dependent manner.…”