Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products

Lung cancer is one of the most common cancers and has a high mortality rate. Due to its high incidence, the clinical management of the disease remains a major challenge. Several reports have documented a relationship between the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway and lung cancer. The recognition of this pathway as a notable therapeutic target in lung cancer is mainly due to its central involvement in the initiation and progression of the disease. Interest in using natural and synthetic medications to target these signaling pathways has increased in recent years, with promising results in vitro, in vivo, and in clinical trials. In this review, we focus on the current understanding of PI3K/AKT/mTOR signaling in tumor development. In addition to the signaling pathway, we highlighted the therapeutic potential of recently developed PI3K/AKT/mTOR inhibitors based on preclinical and clinical trials

Ouabain suppresses the migratory behavior of lung cancer cells.

The migratory capability of cancer cells is one of the most important hallmarks reflecting metastatic potential. Ouabain, an endogenous cardiac glycoside produced by the adrenal gland, has been previously reported to have anti-tumor activities; however, its role in the regulation of cancer cell migration remains unknown. The present study has revealed that treatment with ouabain at physiological concentrations is able to inhibit the migratory activities of human lung cancer H292 cells. The negative effects of ouabain were found to be mediated through the suppression of migration regulatory proteins, such as focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (Akt), and cell division cycle 42 (Cdc42). We found that the observed actions of ouabain were mediated via a reactive oxygen species (ROS)-dependent mechanism because the addition of ROS scavengers (N-acetylcysteine and glutathione) could reverse the effect of ouabain on cell migration. Furthermore, ouabain was shown to inhibit the spheroidal tumor growth and decrease the cancer cell adhesion to endothelial cells. However, the compound had no significant effect on anoikis of the cells. Together, these findings shed light on the understanding of cancer cell biology by exploring the novel function of this endogenous human substance

Prolonged Nitric Oxide Exposure Enhances Anoikis Resistance and Migration through Epithelial-Mesenchymal Transition and Caveolin-1 Upregulation

Nitric oxide (NO) in tumor microenvironment may have a significant impact on metastatic behaviors of cancer. Noncytotoxic doses of NO enhanced anoikis resistance and migration in lung cancer H23 cells via an increase in lamellipodia, epithelial-mesenchymal transition (EMT) markers including vimentin and snail, and caveolin-1 (Cav-1). However, the induction of EMT was found in Cav-1-knock down cells treated with NO, suggesting that EMT was through Cav-1-independent pathway. These effects of NO were consistently observed in other lung cancer cells including H292 and H460 cells. These findings highlight the novel role of NO on EMT and metastatic behaviors of cancer cells