Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases

Abstract

A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)].3HO (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 μM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 μM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 μM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO at concentrations higher than 200 μM displays cytotoxic effects. Graphical abstract Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases.

Do alkaline phosphatases have great potential in the diagnosis, prognosis, and treatment of tumors?

“…In addition to being a potential marker of bone metastases, ALP may also be involved in promoting tumor growth and invasion in lung cancer ( 39 ). In animal studies, inhibiting ALP has been found to reduce lung cancer cell proliferation and migration ( 13 , 40 , 41 ).…”

“…However, it is not just liver metastasis that can cause elevated ALP levels. In fact, patients with pancreatic and lung cancer have also shown increased ALP levels, although the exact mechanism behind this phenomenon remains unclear ( 12 , 13 ). Nonetheless, these findings highlight the importance of monitoring ALP levels in cancer patients as they may provide early indications of disease progression or treatment efficacy.…”

Performance of P2x7 and P2Y Purinergic Receptors as an Inhibiting Factor in the Progression of Pulmonary Neoplastic Cells

“…Studies indicate that the ZnLos complex (zinc and losartan) in concentrations up to 500 μm, acts in the promotion of reactive oxygen species and, consequently, in cell cytotoxicity, triggering the apoptosis of neoplastic cells [21]. Furthermore, this complex regulates BAX protein positively and bcl-XL protein negatively, in addition to acting on caspase-3 release, allowing the greater performance of apoptotic cells [21]. Additionally, metformin, a drug used to treat type 2 diabetics, works by slowing the progression of non-small cell lung cancers by inhibiting the expression of heme oxygenase 1 (HO-1) [22].…”