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

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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.

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ACKNOWLEDGMENTS AND DISCLOSURES

The present study was supported by the National Institute of General Medical Sciences of the US National Institutes of Health (NIH) under Award R01GM099742, and by the US Food and Drug Administration (FDA) under Award U01FD004320. Qing Li received research support from National Natural Science Foundation (NNSF) of China (81001445). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, FDA and NNSF.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, HSFII Room 555, Baltimore, Maryland, 21201, USA

    Qing Li & Yan Shu

  2. Institute of Clinical Pharmacology, Central South University, Hunan, 410078, China

    Qing Li

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  1. Qing Li
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Correspondence to Yan Shu.

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Li, Q., Shu, Y. Pharmacological Modulation of Cytotoxicity and Cellular Uptake of Anti-cancer Drugs by PDE5 Inhibitors in Lung Cancer Cells. Pharm Res 31, 86–96 (2014). https://doi.org/10.1007/s11095-013-1134-0

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