Figure 4.

Potential molecular mechanisms involved in the anticancer effects of the combination gefitinib-loratadine-nebivolol on lung cancer cells. The β-AR and EGFR signaling pathways are proliferative in nature; their overstimulation (β-AR) or oncogenic mutations (EGFR) lead to uncontrolled proliferation of neoplastic cells. However, antagonism of these receptors by nebivolol and gefitinib, respectively, inhibits these pathways. Additionally, nebivolol promotes apoptosis by producing oxidative stress at the mitochondrial level while simultaneously inhibiting mitochondrial respiration and facilitating the degradation of the EGFR receptor in proteasomes through the activation of FBXL2. It is also theorized that it can directly inhibit MEK, in the MAPK proliferative pathway. Furthermore, the lysosomal accumulation of loratadine, an amphiphilic cationic antihistamine (ANHA-CAD) (19) stimulates the release of Ca2⁺ and H⁺, producing inhibition of multidrug-resistant (MDR) proteins by Ca2⁺ and acidification of the cytosol by H⁺, which dephosphorylates and inactivates STAT3, thus inhibiting the STAT3-PI3K-Akt-mTOR signaling. The accumulation of loratadine inside lysosomes stimulates P2RX4, which is responsible for expelling Ca2⁺ into the cytosol, and inhibits ASM (acid sphingomyelinase), which causes an accumulation of ceramides and destabilization of the lysosomal membrane, producing its fragmentation and consequently the release of hydrolases and cathepsins into the cytosol, which favors the initiation of apoptosis and pyroptosis.