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KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation

Authors Lazzari P, Spiga M, Sani M, Zanda M, Fleming IN

Received 20 January 2017

Accepted for publication 27 March 2017

Published 23 May 2017 Volume 2017:5 Pages 45—59


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Dörthe Katschinski

Video abstract presented by Ian N Fleming.

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Paolo Lazzari,1 Marco Spiga,1 Monica Sani,1,2 Matteo Zanda,2,3 Ian N Fleming4

1KemoTech s.r.l., Parco Scientifico della Sardegna, Pula, Cagliari, 2C.N.R. – Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Milano, Italy; 3Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, 4Aberdeen Biomedical Imaging Centre, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland, UK

Purpose: There is an urgent need to develop effective therapies and treatment strategies to treat hypoxic tumors, which have a very poor prognosis and do not respond well to existing therapies.
Methods: A novel hypoxia-targeting agent, KEMTUB012-NI2, was synthesized by conjugating a 2-nitroimidazole hypoxia-targeting moiety to a synthetic tubulysin, a very potent antimitotic. Its hypoxic selectivity and mode of action were studied in breast cancer cell lines.
Results: KEMTUB012-NI2 exhibited a similar selectivity for hypoxic cells to that of tirapazamine, a well-established hypoxia-targeting agent, but was >1,000 times more potent in cell cytotoxicity assays. The hypoxia-targeting mechanism for both KEMTUB012-NI2 and tirapazamine was selective and mediated by one-electron reductases. However, while cytochrome p450 reductase (POR) downregulation could inhibit tirapazamine cytotoxicity, it actually sensitized hypoxic cells to KEMTUB012-NI2.
Conclusion: KEMTUB012-NI2 is a potent new agent that can selectively target hypoxic cancer cells. The hypoxia selectivity of KEMTUB012-NI2 and tirapazamine appears to be differentially activated by reductases. Since reductases are heterogeneously expressed in tumors, the different activation mechanisms will allow these agents to complement each other. Combining POR downregulation with KEMTUB012-NI2 treatment could be a new treatment strategy that maximizes efficacy toward hypoxic tumor cells while limiting systemic toxicity.

Keywords: breast cancer, tubulysin, anti-mitotic, hypoxia, cell death, reductase

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