AB063. Potential synergistic effect by combination of PED-4 and PED-5 inhibitors plus theophylline in lung cancer?

Background: Lung cancer remains the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Differentiation-based therapeutics (Methylxanthines) and phosphodiesterase inhibitors (type 4 and 5), have been implicated in cancer treatment. Our objectives were to capture any potential anti-tumor effect of these drug combinations with chemotherapeutic agents in vitro.

Methods: Theophylline as Methylxanthines, Roflumilast as phosphodiesterase type 4 (PED-4) inhibitor and Sildenafil as phosphodiesterase type 5 (PED-5) inhibitor are the drugs that we combined with the chemotherapeutic agents (Docetaxel, Cisplatin and Carboplatin) in vitro. Lung cancer cell lines (NCI-H1048-small cell lung cancer, A549-non-small cell lung cancer) were purchased from ATCC LGC Standards. At indicated time-point, following 24 and 48 h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism.

Results: In Small cell lung cancer cells, following 48 h incubation, combinations of carboplatin and roflumilast (P<0.05), carboplatin with roflumilast and sildenafil (P<0.0001), carboplatin with theophylline and sildenafil (P<0.001), showed increased apoptosis when compared to carboplatin alone. The only combination that showed increased apoptosis following 24 h incubation was carboplatin with theophylline (P<0.0001). Moreover, cisplatin combined with roflumilast, theophylline and sildenafil resulted in increased apoptosis after 48 h incubation when compared with cisplatin alone (P<0.05). In non-small cell lung cancer cells, the 24 h incubation was not enough to induce satisfactory apoptosis, except for the combination of cisplatin with roflumilast and theophylline. However, following 48 h incubation, carboplatin plus sildenafil, carboplatin plus sildenafil, theophylline and roflumilast showed more cytotoxicity when compared to carboplatin alone (P<0.001). In addition, the combination of docetaxel plus theophylline and roflumilast was found with higher cytotoxicity when compared to docetaxel alone after 48 h treatment (P<0.001).

Conclusions: Depending on the drug, the synergistic effect of PED-4 and PED-5 inhibitors plus theophylline with chemotherapeutic agents has been demonstrated in lung cancer. Our suggestion is that these combinations could be used as additive and maintenance treatment in combination to antineoplastic agents in lung cancer patients.

Keywords: Lung cancer; combination therapy; phosphodiesterase inhibitors