Improving early detection, decreasing tobacco smoking and developing better therapies are all important strategies for combatting lung cancer, but drug-targeted lung cancer prevention is another option. Kyung-Hee Chun et al. now show that AKT — a downstream component of the phosphatidylinositol 3-kinase (PI3K) pathway, which is important in regulating cell proliferation and apoptosis — is constitutively active in an in vitro lung carcinogenesis progression model. They further report that deguelin — a natural plant product drug — inhibits activated AKT in this model system, so showing potential as a lung cancer chemoprevention agent.

Ho-Young Lee and colleagues used normal, immortalized, premalignant and malignant human bronchial epithelial (HBE) cell lines. Deguelin inhibited cell proliferation — cells accumulated in the G2–M phase of the cell cycle — and induced apoptosis in the premalignant and malignant cell lines in a dose- and time-dependent manner, but had no adverse effects on normal or immortalized HBE cells. Levels of activated phosphorylated AKT were higher in the transformed cells than in normal cells and, at concentrations that might be attainable in vivo, the authors showed that deguelin decreased levels of phosphorylated AKT without affecting the total levels of the protein. Deguelin also decreased PI3K activity by about half, although it took longer to do so than inhibition of AKT, indicating that deguelin might inhibit AKT activity through both PI3K-dependent and -independent mechanisms.

So, is the AKT pathway a specific target of deguelin? Treatment with deguelin did not affect the activity of other components of kinase pathways, such as mitogen-activated protein kinase (MAPK), extracellular signal-related kinase 1/2 (ERK1/2) or JUN N-terminal kinase (JNK). In addition, when one of the premalignant cell lines was infected with an adenovirus expressing constitutively active AKT and treated with deguelin, inhibition of growth and triggering of apoptosis was much reduced.

As deguelin belongs to a class of agents that are used as insecticides, which have been associated with cardiac and other toxicities in humans, thorough evaluation of possible toxic effects will be key to the development of the compound for lung cancer prevention. Constitutive activation of AKT occurs frequently in non-small-cell lung cancer in humans, so we await further investigation of how deguelin inhibits AKT with interest.