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

Abstract

Non‐small lung cell carcinoma has a high morbidity and mortality rates. The elective treatment for stage III and IV is cisplatinum that conveys serious toxic side effects. Vanadium compounds are metal molecules with proven antitumor activity that depends on its valence. Therefore, a better understanding of the mechanism of action of vanadium compounds is required. The aim of our study was to investigate the mechanisms of cell death induced by sodium metavanadate (NaVO3 [V(+5)]) and vanadyl sulfate (VOSO4 [(+4)]), both of which have reported apoptotic‐inducing activity. We exposed the A549 cell line to various concentrations (0‐100 μM) and to different exposure times to each compound and determined the cell viability and expression of caspases, reactive oxygen species (ROS) production, Bcl2, Bax, FasL and NO. Our results showed that neither compounds modified the basal expression of caspases or pro‐ and anti‐apoptotic proteins. The only change observed was the 12‐ and 14‐fold significant increase in ROS production induced by NaVO3 and VOSO4, respectively, at 100 μm concentrations after 48 hours. Our results suggest that classical apoptotic mechanisms are not related to the cell death induced by the vanadium compounds evaluated here, and showed that the higher ROS production was induced by the [(+4)] valence compound. It is possible that the difference will be secondary to its higher oxidative status and thus higher ROS production, which leads to higher cell damage. In conclusion, our results suggest that the efficacy of the cell death mechanisms induced by vanadium compounds differ depending on the valence of the compound.

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

“…However, the higher ROS level was induced by complexes containing vanadium(+IV) in the coordination center [46]. These results suggest that the efficacy of the ROS generation induced by vanadium compounds depends on the oxidation state of the vanadium cation presented in the coordination sphere of the complex [46]. For peroxovanadate complexes, the results are consistent.…”

“…In one of the most recent studies, vanadium salts, sodium metavanadate NaVO 3 (36) and vanadium(IV) sulfate oxideVOSO 4 (37) significantly increased the ROS level in human lung cancer cells. However, the higher ROS level was induced by complexes containing vanadium(+IV) in the coordination center [46]. These results suggest that the efficacy of the ROS generation induced by vanadium compounds depends on the oxidation state of the vanadium cation presented in the coordination sphere of the complex [46].…”

“…The complex with phenanthroline (45) showed the highest cytotoxic activity which correlated with the strongest increase of ROS [51]. Interestingly, in studies performed by our group, the same vanadium complex (45)(46)(47) also induced the ROS generation in a human pancreatic cancer cell line [52]. In another study, an oxovanadium (IV/V) complex with a galactomannan derivative (polysaccharides) (48 and 49) showed cytotoxicity against a human liver cancer cell line by decreasing the mitochondrial membrane potential and increasing the ROS levels [53].…”

“…Induction of oxidative stress may lead to apoptotic cell death [95]. Vanadium inorganic salts, namely NaVO 3 (36) and VOSO 4 (37), exhibited apoptotic-inducing cytotoxicity against non-small lung cell carcinoma cells with simultaneous increase of ROS level [46]. Pisano et al have shown that both the inorganic anion vanadate(V) (62) and the vanadium complex with pyridinonate (63) induced apoptosis through generation of ROS in malignant melanoma cells [78].…”

Oxidative Stress and Vanadium

“…Studies in vivo and in vitro showed that vanadium compounds induce cell death in leukemia [21], lung cancer [22] cervical and breast carcinoma [23], neuroblastoma [24], liver carcinoma [25], osteosarcoma [26], and pancreatic ductal adenocarcinoma [27]. In vitro studies demonstrated that the cell lines stimulated with vanadium compounds produce H 2 O 2 and O 2 and induce autophagy, necroptosis, and mitotic catastrophe [27].…”