Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells

Abstract

Purpose Previous research has led to the recognition of a cGMP signaling pathway governing drug transport. This study is to investigate whether inhibitors of phosphodiesterase type 5 (PDE5), which increase intracellular cGMP levels, modulate the cytotoxicity and uptake of anti-cancer drugs in cancer cells. Methods The experiments were conducted with and without PDE5 inhibitors: dipyridamole, vardenafil, and/or sildenafil. The cytotoxicity of doxorubicin, cisplatin and oxaliplatin was determined in multiple cancer cell lines derived from different tissues. The cellular uptake of structurally diverse compounds was further examined in lung cancer cells with and without various endocytotic inhibitors. The tumor accumulation and the anti-tumor effect of trastuzumab were examined in a lung cancer xenograft mouse model. Results Dipyridamole could modulate the cytotoxicity of doxorubicin, cisplatin, and oxaliplatin in cancer cells. Particularly, PDE5 inhibitors increased cellular uptake of structurally diverse compounds into lung cancer cells both in vitro and in vivo. The effect of vardenafil on drug uptake could be blocked by endocytotic inhibitors. The growth of lung cancer xenograft in nude mice was significantly suppressed by addition of vardenafil to trastuzumab treatment. Conclusion PDE5 inhibitors may increase the efficacy of anti-cancer drugs by increasing endocytosis-mediated cellular drug uptake, and thus serve as adjuvant therapy for certain cancers such as lung cancer.

PDE5 Inhibitors-Loaded Nanovesicles: Physico-Chemical Properties and In Vitro Antiproliferative Activity

“…Moreover the efficacy of the encapsulated drug even in those cancer cells carrying a genetic alteration associated with an aggressive behavior [ 34 , 35 ] may have an important implication for potential personalized therapeutic approaches. At present, there are some reports which suggest the potential use of PDE5 inhibitors as antineoplastic agents [ 10 , 36 , 37 ], but the possible impact of adverse dose-dependent effects owing to their vasodilatatory action has not yet been investigated. If confirmed even in vivo , such a property of our new formulations which would permit the adoption of a low-dosage regimen of the drugs could help to overcome this fundamental issue.…”

Repurposing drugs in oncology (ReDO)—selective PDE5 inhibitors as

“…Sildenafil, vardenafil and dipyridamole were investigated by Li and Shu [ 40 ] as potential enhancers of response to cytotoxic chemotherapy drugs in the H1915 lung cancer cell line and in a murine model. In vitro results showed that all three drugs tested, (at concentrations: 20 μM vardenafil, 100 μM sildenafil and 20 μM dipyridamole), increased the uptake of doxorubicin and carboplatin.…”

Phosphodiesterase type 5 and cancers: progress and challenges

“…In orthotopic lung cancer model systems, exisulind in association with docetaxel significantly induced apoptosis, reduced tumor growth and metastasis, and increased survival [ 10 , 205 , 206 ]. PDE5 inhibitors also improved the chemosensitivity of anti-cancer agents by increasing endocytosis-mediated cellular drug uptake in lung cancer cells; for instance, oral administration of the PDE5 inhibitor vardenafil significantly increases the accumulation and enhances the anti-tumor effect of trastuzumab in a xenograft mouse model of lung cancer [ 207 ]. Another study showed that sildenafil was able to enhance the anti-tumor effects of the standard of care drug pemetrexed in NSCLCs.…”