Non-Small-Cell Lung Cancer (NSCLC) is considered one of the most frequently diagnosed
cancers and the leading cause of
cancer-related deaths worldwide. Despite the undoubted therapeutic advances that have occurred in clinical practice over time, due to its high degree in both heterogeneity and resistance, NSCLC remains largely incurable. As a natural cAMP elevating agent,
Forskolin has shown anti-
cancer properties in different
tumor types, thus supposing its possible usage in treating
malignancies. In this study, we investigated the
Forskolin outcome in H1299 and A549 NSCLC cell lines, either alone or in combination with
Paclitaxel. We proved that
Forskolin impairs cell growth and migration ability of these cells, concurrently. Albeit with a different extent between H1299 and A549, changes in cell-cycle progression and epithelial-mesenchymal markers were observed in response to
Forskolin administration. Interestingly, comparable cell growth impairment was also obtained with the
cAMP phosphodiesterase inhibitor
IBMX, while the employment of
adenylyl cyclase inhibitor SQ22536 counteracted, at least in part, the
Forskolin-mediated anticancer effects. Besides as a single agent, we also demonstrated that
Forskolin strongly enhances
Paclitaxel-induced cytotoxicity, affecting cell death mainly via apoptosis induction. Notably, H89-mediated
protein kinase A (PKA) inhibition further deteriorated the combination outcome. Altogether, our data designate
Forskolin as a possible anticancer molecule in NSCLC, and recognize the
adenylyl cyclase/cAMP axis as one of the pathways involved in. Although achieved at preclinical stage, our findings encourage the design of future studies aimed at further exploring the
Forskolin employment in NSCLC treatment.