J Cancer 2017; 8(18):3648-3656. doi:10.7150/jca.21783

Research Paper

Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer

Kalliopi Domvri1, Konstantinos Zarogoulidis1, Nikolaos Zogas3, Paul Zarogoulidis1✉, Savvas Petanidis4, Konstantinos Porpodis1, Efrosini Kioseoglou3, Wolfgang Hohenforst-Schmidt2

1. Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
2. Sana Clinic Group Franken, Department of Cardiology / Pulmonology / Intensive Care / Nephrology, ''Hof'' Clinics, University of Erlangen, Hof, Germany
3. Gene and Cell Therapy Center, Hematology Department-Bone Marrow Transplantation Unit, “G. Papanikolaou” General Hospital, Thessaloniki, Greece
4. Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Domvri K, Zarogoulidis K, Zogas N, Zarogoulidis P, Petanidis S, Porpodis K, Kioseoglou E, Hohenforst-Schmidt W. Potential synergistic effect of phosphodiesterase inhibitors with chemotherapy in lung cancer. J Cancer 2017; 8(18):3648-3656. doi:10.7150/jca.21783. Available from http://www.jcancer.org/v08p3648.htm

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Purpose: 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 (PDE4) inhibitor and Sildenafil as phosphodiesterase type 5 (PDE5) 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-SCLC, A549- Non-small cell lung cancer-NSCLC) were purchased from ATCC LGC Standards. At indicated time-point, following 24h and 48h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism.

Results: In SCLC, following 48h incubation, platinum combinations of carboplatin with roflumilast and sildenafil (p<0.001) and carboplatin with theophylline and sildenafil showed increased apoptosis when compared to carboplatin alone. Concerning the combinations of cisplatin, when combined with roflumilast, theophylline and sildenafil appeared with increased apoptosis of that alone (p<0.001, 24h and 48h incubation). In NSCLC, the 24h incubation was not enough to induce satisfactory apoptosis, except for the combination of cisplatin with roflumilast and theophylline (p<0.05) when compared to cisplatin alone. However, following 48h incubation, carboplatin plus sildenafil, carboplatin plus sildenafil, theophylline and roflumilast showed more cytotoxicity when compared to carboplatin alone (p<0.001). Docetaxel combinations showed no statistically significant results.

Conclusion: The synergistic effect of PDE inhibitors with platinum-based 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, theophylline, roflumilast, sildenafil, cisplatin, carboplatin, synergistic effect