Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma
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Jennifer Bryant1,*, Nikolaos Batis1,*, Anna Clara Franke1, Gabriella Clancey1, Margaret Hartley1, Gordon Ryan1, Jill Brooks1, Andrew D. Southam4,5, Nicholas Barnes2,7, Joanna Parish2, Sally Roberts2, Farhat Khanim6, Rachel Spruce1,# and Hisham Mehanna1,3,#
1 Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK
2 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
3 University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
4 School of Biosciences, University of Birmingham, Birmingham, UK
5 Phenome Centre Birmingham, University of Birmingham, Birmingham, UK
6 School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
7 School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
* Joint first authors
# Joint senior authors
|Hisham Mehanna,||email:||[email protected]|
|Nikolaos Batis,||email:||[email protected]|
Keywords: head and neck cancer; drug repurposing; drug repositioning; quinacrine; mepacrine
Received: April 13, 2019 Accepted: July 17, 2019 Published: August 27, 2019
Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need.
We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo models (xenograft tumors in NOD/SCID/gamma mice).
Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63–1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/– irradiation) alone. In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days (p < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans.
Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.
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