This study aimed to clarify the impact of HA and L-NAME on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway in A549 human lung adenocarcinoma and MDA-MB-231 breast cancer triple-negative cells, with particular emphasis on the tumor necrosis factor-alpha (TNFα)/cyclooxygenase-2 (COX-2) and vascular endothelial growth factor A (VEGFα)/matrix metalloproteinase-2 (MMP-2) pathways. This evidence concerns the gene PTGS2 and breast carcinoma.