Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth
Received 28 April 2018
Accepted for publication 19 June 2018
Published 7 September 2018 Volume 2018:12 Pages 2805—2814
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Anastasios Lymperopoulos
Franck Gallardo,1 Bernard Mariamé,2 Remi Gence,3 Anne-Francoise Tilkin-Mariamé4
1NeoVirTech, SAS, Institut for Advanced Technology in Life Science (ITAV), Toulouse, France; 2ITAV USR3505 CNRS/LBME, UMR 5099 CNRS, Toulouse, France; 3INSERM UMR 1037, CRCT, University of Toulouse, Toulouse, France; 4INSERM 1220, IRSD, University of Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
Purpose: The Epstein–Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases.
Methods: Search for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers.
Results: We show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice.
Conclusion: Macrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect.
Keywords: nasopharyngeal carcinoma, ivermectin, macrocyclic lactones, P21-activated kinase 1, cytotoxicity
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