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The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

Authors Meier-Stephenson V, Riemer J, Narendran A

Received 8 March 2017

Accepted for publication 19 April 2017

Published 16 May 2017 Volume 2017:10 Pages 2581—2593

DOI https://doi.org/10.2147/OTT.S136484

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Carlos Vigil Gonzales

Vanessa Meier-Stephenson,1,2 Justin Riemer,1,2 Aru Narendran1–3

1Department of Oncology, Cumming School of Medicine, University of Calgary, 2Department of Pediatrics, Alberta Children’s Hospital, 3Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Laboratory, Calgary, AB, Canada

Purpose: Refractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.
Materials and methods: A comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.
Results: Several of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1–24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).
Conclusion: Here, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

Keywords: nelfinavir, HIV protease inhibitors, pediatric leukemia, endoplasmic reticulum stress, autophagy, apoptosis

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